JP4294960B2 - Cyclin-dependent kinase inhibitors as anticancer agents - Google Patents

Abstract

The present invention relates to 2-substituted 4-heteroaryl-pyrimidines, their preparation, pharmaceutical compositions containing them and their use as inhibitors of cyclin-dependent kinases (CDKs) and hence their use in the treatment of proliferative disorders such as cancer, leukaemia, psoriasis and the like.

Description

    The present invention relates to 2-substituted 4-heteroaryl-pyrimidines, their preparations, pharmaceutical compositions containing them and their use in the treatment of proliferative diseases such as cancer, leukemia, psoriasis.

  A description of several 4,5,6-substituted-N- (substituted-phenyl) -2-pyrimidinamines having anti-asthma properties is found in EP 233461 (Patent Document 1). 4-heteroaryl-N- (3-substituted-phenyl) has antiproliferative properties and inhibits protein kinase C and epidermal growth factor receptor-related tyrosine protein kinase (EGF-R-TPK) as well as CDK1 / cyclin B A description of several 2-pyrimidineamines is found in WO 95/09847 (Patent Document 2), and examples of heteroaryl include pyridyl and indolyl.

  J. Med. Chem. (1993) Vol. 36, pp. 271-2725, Paul, R. et al. Describes a further class of phenylamino-pyrimidines with anti-inflammatory activity. ing. Such compounds include an unsubstituted pyrrole group, a monosubstituted 2-thienyl group, and a dimethyl-3-furyl group at the 4-position of the pyrimidine ring.

The object of the present invention is to provide a further class of N-phenyl-2-pyrimidine antiproliferative compounds. Surprisingly, it has been found that the compounds according to the invention are not inhibitors of protein kinase C. As described below, the activity of the compounds of the invention is shown as inhibiting cell proliferation in cell lines and / or inhibiting cyclin dependent kinase enzymes.
European Patent Application No. 233461 International Publication No. WO95 / 09847 Pamphlet J. Med. Chem. (1993) Vol. 36, pp. 271-2725, Paul, R. et al.

  The present invention is primarily based on the general formula (I)

[Wherein ^one of X ¹ and X ^{2 represents} NH , and the other represents CR ⁹ ;
Z represents NH, NHCO, NHSO ₂ , NHCH ₂ , CH ₂ , CH ₂ CH ₂ , or CH═CH;
R ¹ , R ² , R ³ and R ⁹ are each independently a hydrogen atom, alkyl, aryl, aralkyl, heterocycle, halogeno, NO ₂ , CN, OH, alkoxy, aryloxy, (R ′ ″) _n NH ₂ , (R ′ ″) _n NH—R ′, (R ′ ″) _n N— (R ′) (R ″), NH-aryl, N- (aryl) ₂ , COOH, COO—R ', COO- _{aryl, CONH 2, CONH-R'} , CON- (R ') (R''), CONH- aryl, CON- _{(aryl) 2, SO 3 H, SO} 2 NH 2, CF 3, CO —R ′ or CO-aryl (alkyl, aryl, aralkyl, and heterocyclic groups are further halogeno, NO ₂ , CN, OH, O-methyl, NH ₂ , COOH, CONH _2; , and may be substituted with one or more groups selected from CF ₃₎ Wherein at least one of the radicals R ^1, R ² and R ⁹ represents a group other than a hydrogen atom;
R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently a hydrogen atom, substituted or unsubstituted lower alkyl, halogeno, NO ₂ , CN, OH, substituted or unsubstituted alkoxy, NH ₂ , NH—R ′, N— (R ′) (R ″), COOH, COO—R ′, CONH ₂ , CONH—R ′, CON— (R ′) (R ″), SO ₃ H, SO ₂ NH ₂ or CF ₃ is shown;
R ', R''andR''' each independently represent the same or different alkyl group, n Ru 0 or 1 der. And a pharmaceutically acceptable salt thereof.

  The term “alkyl” as used herein includes both straight and branched alkyl groups having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl. And the term “lower alkyl” is used similarly for groups having 1 to 4 carbon atoms.

  The term “aryl” is used to include groups having 6 to 10 carbon atoms, such as phenyl, naphthyl, and the like.

  The term “aralkyl” is used as a combination of the terms alkyl and aryl described above.

Preferred compounds represented by Formula I are those having a mono-, di-, or tri-substituted pyrrole radical that is bonded to the pyrimidine ring by any one of the cyclic carbon atoms. Preferred pyrrole radicals are those that are di- or tri-substituted with a pyrrol-3-yl group (ie, X ¹ is CR ⁹ and X ² is NR ¹⁰ , preferably NH).

The pyrrole group may be substituted by R ¹ , R ² , R ⁹ and R ¹⁰ . R ¹ , R ² , and optionally R ⁹ and R ¹⁰ are each independently a hydrogen atom, alkyl, aryl, aralkyl, heterocycle, halogeno, NO ₂ , CN, OH, alkoxy, aryloxy, (R _{''') nNH 2, (} R''') nNH-R ', (R''') nN- (R ') (R''), NH- aryl, N- (aryl) _2, COOH, COO -R ', COO- _{aryl, CONH 2, CONH-R'} , CON- (R ') (R''), CONH- aryl, CON- _{(aryl) 2, SO 3 H, SO} 2 NH 2, CF 3 , CO-R 'or CO- an aryl, alkyl, aryl, each group of the aralkyl and the heterocyclic further halogeno, NO _2, CN, OH, O-methyl _{(O-methyl), NH 2} , COOH, CONH _2, and it is substituted with one or more groups selected from CF ₃ It can have. Most preferably, R ¹⁰ is a hydrogen atom.

R ¹ , R ² and R ⁹ are each independently a hydrogen atom, halogeno, NO ₂ , CN, (R ′ ″) nN— (R ′) (R ″), CONH ₂ , C1-C4 alkyl, And more preferably selected from heterocyclic rings. Of R ¹ , R ² and R ⁹ , it is preferred that at least one, more preferably at least 2 or 3 is not a hydrogen atom.

R ¹ preferably represents a hydrogen atom, CN, halogeno, nitro, alkylamino, or a heterocyclic group. When R ¹ is halogeno, it is preferably selected from chloro or bromo. When R ¹ is alkylamino, it is preferably diethylaminomethyl or dimethylaminomethyl. When R ¹ is a heterocyclic group, it is preferably morpholin-4-ylmethyl or 4-methyl-piperazin-1-ylmethyl. R ¹ is most preferably a hydrogen atom or CN.

When R ¹ is as defined above, R ² and R ⁹ are preferably both lower alkyl, preferably methyl.

The Z group is preferably NH, NHSO ₂ and NHCH ₂ , most preferably NH.

The phenyl substituents R ^{4 to} R ⁸ are each independently a hydrogen atom, halogeno, nitro, amino, aminoalkyl, hydroxy, alkoxy, carbamoyl, sulfamyl, CN, N (R ′) (R ″), C ₁₋ Selected from ₄ alkyl and substituted C _1-4 alkyl.

R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently a hydrogen atom, unsubstituted lower alkyl, halogeno, NO ₂ , CN, OH, N- (R ′) (R ″) Or CF ₃ , where R ′, R ″ and R ′ ″ each independently represent the same or different alkyl group, and n is 0 or 1.

R ^{4 to} R ⁸ are each independently selected from a hydrogen atom, F, NH ₂ , NO ₂ , OH, Cl, Br, I, CN, CH ₂ OH, CF ₃ , and dimethylamino, Even more preferred. Of the preferred examples of R ^{4 to} R ⁸ , R ⁴ and R ⁸ are most preferably hydrogen atoms.

Thus, in a particularly preferred embodiment, the phenyl group is in the 2, 3 or 4 position a hydrogen atom, F, NH ₂ , NO ₂ , OH, Cl, Br, I, CN, CH ₂ OH, CF ₃ or OMe. 2- [N- (phenyl)]-4- (2,4-dimethylpyrrol-3-yl) pyrimidinamine substituted with at least one of the above.

In the above embodiment, whether the phenyl group is mono-substituted at any of the 2, 3 or 4 positions by F, NH ₂ , NO ₂ , OH, Cl, Br, I, CH ₂ OH, CN, CF ₃ or OMe Or alternatively by 2,4-difluoro, 3,5-difluoro, 3,4-difluoro, 2,4-dichloro, 3,5-dichloro, 3,4-dichloro, or 4-chloro-3-trifluoromethyl. It is preferably substituted.

In an even more preferred embodiment, the phenyl group is substituted in the ₂ , 3 or 4 position with at least one of F, NH (CH ₃ ) ₂ , NO ₂ , OH, Cl, Br, I, or CF _3. 2- [N- (phenyl)]-4- (3,5-dimethyl-1H-pyrrole-2-carbonitrile) pyrimidinamine is included.

Within the scope of the above embodiments, the phenyl group is monosubstituted at either the 3 or 4 position with F, NH (CH ₃ ) ₂ , NO ₂ , OH, I, or CF ₃ , or 4-methyl- Disubstituted by 3-nitro, 3-iodo-4-methyl, 4-chloro-3-methyl, 3-hydroxy-4-methyl, 4-fluoro-3-methyl, or 4-methyl-3-fluoro It is preferable.

  Even more preferred embodiments include the following.

Preferably the phenyl group is monosubstituted at the 4-position by F, NH (CH ₃ ) ₂ , NO ₂ , OH, I or CF ₃ , more preferably by a fluoro group or NH (CH ₃ ) ₂ group 2 -[N- (phenyl)]-4- (2,4-dimethyl-5-nitro-1H-pyrrol-3-yl) -pyrimidinamine.

Preferably the phenyl group is mono-substituted at the 3 or 4 position by F, NH (CH ₃ ) ₂ , NO ₂ , OH, I or CF ₃ , more preferably by a 4-fluoro group or a 3-nitro group. 2- [N- (Phenyl)]-4- (2,4-dimethyl-5-halogeno-1H-pyrrol-3-yl) -pyrimidinamine (the halogeno group is preferably chloro or bromo).

Preferably 2- [N- (phenyl)] monosubstituted at the 4-position by F, NH (CH ₃ ) ₂ , NO ₂ , OH, I, or CF ₃ , more preferably by a fluoro group -4- (2,4-dimethyl-5-dialkylaminoalkyl-1H-pyrrol-3-yl) -pyrimidinamine (dialkylaminoalkyl group is preferably diethylaminomethyl or dimethylaminomethyl).

Preferably 2- [N- (phenyl)] monosubstituted by a fluoro group at the 4-position, more preferably by F, NH (CH ₃ ) ₂ , NO ₂ , OH, I or CF ₃ , more preferably a fluoro group -4- (2,4-dimethyl-5- (heterocyclic) -1H-pyrrol-3-yl) -pyrimidinamine (the heterocyclic group is a 5-morpholin-4-ylmethyl group or 4-methyl-piperazine-1 -It is preferably an ylmethyl group).

Most preferably, the compound of the invention is selected from:
[4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrole-3 -Yl) -pyrimidin-2-yl]-(3-nitro-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-iodo) -Phenyl) -amine (3,4-difluoro-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (4-chloro-phenyl)- [4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (3,5-difluoro-phenyl)-[4- (2,4-dimethyl-1H-pyrrole) -3-yl) -pyrimidin-2-y ] -Amine 4- [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-ylamino] -phenol 3- [4- (2,4-dimethyl-1H-pyrrole-3- Yl) -pyrimidin-2-ylamino] -phenol (2,4-difluoro-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (2 , 4-Dichloro-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (4-chloro-3-trifluoromethyl-phenyl)-[ 4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl ]-(4-Triff Oromethyl-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(3-trifluoromethyl-phenyl) -amine (3-chloro-phenyl) -[4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine
N- [4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -N ′, N′-dimethyl-benzene-1,4-diamine (3-chloro-4- Iodo-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine [4- (2,4-dimethyl-1H-pyrrol-3-yl) -Pyrimidin-2-yl]-(3-fluoro-4-iodo-phenyl) -amine 3,5-dimethyl-4- [2- (3-nitro-phenylamino) -pyrimidin-4-yl] -1H- Pyrrole-2-carbonitrile 4- [2- (4-Fluoro-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-hydroxy -Phenylamino) -pyrimidine 4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 3,5-dimethyl-4- [2- (4-trifluoromethyl-phenylamino) -pyrimidin-4-yl] -1H- Pyrrole-2-carbonitrile 4- [2- (4-Iodo-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-hydroxy -Phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 3,5-dimethyl-4- [2- (4-methyl-3-nitro-phenylamino)- Pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile 4- [2- (3-iodo-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H Pyrrole-2-carbonitrile 4- [2- (4-Chloro-3-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-Hydroxy-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-fluoro-3-methyl-phenylamino) ) -Pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-fluoro-4-methyl-phenylamino) -pyrimidin-4-yl] -3, 5-Dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-dimethylamino-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2 -Carbonitrile 4- [2- (4-fluoro-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid amide [4- (3,5-dimethyl-1H -Pyrrol-2-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine (4-fluoro-phenyl)-[4- (1,2,4-trimethyl-1H-pyrrole-3- Yl) -pyrimidin-2-yl] -amine [4- (2,4-dimethyl-5-nitro-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine N- [4- (2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl) -pyrimidin-2-yl] -N ′, N′-dimethyl-benzene-1,4-diamine [4- (5-amino-2,4-dimethyl 1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (5-bromo-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidine- 2-yl]-(4-fluoro-phenyl) -amine [4- (5-bromo-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(3-nitro-phenyl) ) -Amine [4- (5-chloro-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (5-diethylaminomethyl) -2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (5-dimethylaminomethyl-2,4-dimethyl-1H- Pyrrole-3 Yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (2,4-dimethyl-5-morpholin-4-ylmethyl-1H-pyrrol-3-yl) -pyrimidin-2- Yl]-(4-fluoro-phenyl) -amine
[4- [2,4-Dimethyl-5- (4-methyl-piperazin-1-ylmethyl) -1H-pyrrol-3-yl] -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine above The structure of the compound is shown in FIG.

Particularly preferred compounds observed are those that have a CDK2 / cyclin E IC ₅₀ of less than 5 μM (± 0.05) and are CDK inhibitors and include the following compounds:
[4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrole-3 -Yl) -pyrimidin-2-yl]-(3-nitro-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-iodo) -Phenyl) -amine (3,4-difluoro-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (4-chloro-phenyl)- [4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (3,5-difluoro-phenyl)-[4- (2,4-dimethyl-1H-pyrrole) -3-yl) -pyrimidin-2-y ] -Amine 4- [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-ylamino] -phenol 3- [4- (2,4-dimethyl-1H-pyrrole-3- Yl) -pyrimidin-2-ylamino] -phenol [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-trifluoromethyl-phenyl) -amine (3 -Chloro-4-iodo-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine [4- (2,4-dimethyl-1H-pyrrole) -3-yl) -pyrimidin-2-yl]-(3-fluoro-4-iodo-phenyl) -amine 3,5-dimethyl-4- [2- (3-nitro-phenylamino) -pyrimidin-4- Il] -1H- Roll-2-carbonitrile 4- [2- (4-fluoro-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-hydroxy -Phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 3,5-dimethyl-4- [2- (4-trifluoromethyl-phenylamino) -pyrimidine- 4-yl] -1H-pyrrole-2-carbonitrile 4- [2- (4-iodo-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-Hydroxy-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 3,5-dimethyl-4- [2- (4-Methyl-3-nitro-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile 4- [2- (3-iodo-4-methyl-phenylamino) -pyrimidine-4- Yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-chloro-3-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H- Pyrrole-2-carbonitrile 4- [2- (3-hydroxy-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-fluoro-4-methyl-) Enylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-dimethylamino-phenylamino) -pyrimidin-4-yl] -3,5- Dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-fluoro-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid amide (4-fluoro -Phenyl)-[4- (1,2,4-trimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine [4- (2,4-dimethyl-5-nitro-1H-pyrrole) -3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine N- [4- (2,4-dimethyl-5-nitro-1H-pyrrol-3-yl) -pyrimidine- -Yl] -N ', N'-dimethyl-benzene-1,4-diamine [4- (5-bromo-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-( 4-Fluoro-phenyl) -amine [4- (5-bromo-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(3-nitro-phenyl) -amine [4- (5-Chloro-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (5-diethylaminomethyl-2,4-dimethyl) -1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (5-dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl) -Pyrimidin-2-yl] (4-Fluoro-phenyl) -amine [4- (2,4-dimethyl-5-morpholin-4-ylmethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -Amines and {4- [2,4-dimethyl-5- (4-methyl-piperazin-1-ylmethyl) -1H-pyrrol-3-yl] -pyrimidin-2-yl}-(4-fluoro-phenyl) ) -Amine

Among the above compounds, those having an IC _{50 of} CDK2 / cyclin E of less than 1 μM (± 0.05) and becoming CDK inhibitors include the following compounds.
[4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrole-3 -Yl) -pyrimidin-2-yl]-(3-nitro-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-iodo) -Phenyl) -amine [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-trifluoromethyl-phenyl) -amine 3,5-dimethyl-4- [2- (3-Nitro-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile 4- [2- (4-fluoro-phenylamino) -pyrimidin-4-yl] -3, 5-Dimethyl-1H-pi 2-carbonitrile 4- [2- (4-hydroxy-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 3,5-dimethyl-4- [2- (4-Trifluoromethyl-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile 4- [2- (4-iodo-phenylamino) -pyrimidin-4-yl]- 3,5-Dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-hydroxy-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 3 , 5-Dimethyl-4- [2- (4-methyl-3-nitro-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile 4- [2- (3-yo Do-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-chloro-3-methyl-phenylamino) -pyrimidine -4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-hydroxy-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl -1H-pyrrole-2-carbonitrile 4- [2- (4-fluoro-3-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-Fluoro-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-dimethylamino No-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-fluoro-phenylamino) -pyrimidin-4-yl] -3, 5-Dimethyl-1H-pyrrole-2-carboxylic acid amide [4- (2,4-dimethyl-5-nitro-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) Amine N- [4- (2,4-dimethyl-5-nitro-1H-pyrrol-3-yl) -pyrimidin-2-yl] -N ′, N′-dimethyl-benzene-1,4-diamine [ 4- (5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (5-bromo-2,4- Dimethyl-1H-pyrrole-3- ) -Pyrimidin-2-yl]-(3-nitro-phenyl) -amine [4- (5-chloro-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-( 4-Fluoro-phenyl) -amine [4- (5-diethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4 -(5-dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine, and [4- (2,4-dimethyl) -5-morpholin-4-ylmethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine

Even more preferred among the above compounds are those in which the IC _{50 of} CDK2 / cyclin E is less than 0.5 μM (± 0.05) and become CDK inhibitors, and the following compounds are included.
[4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(3-nitro-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrole-3 -Yl) -pyrimidin-2-yl]-(4-iodo-phenyl) -amine 3,5-dimethyl-4- [2- (3-nitro-phenylamino) -pyrimidin-4-yl] -1H-pyrrole 2-carbonitrile 4- [2- (4-fluoro-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-hydroxy- Phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 3,5-dimethyl-4- [2- (4-trifluoromethyl-phenylamino) -pyrimidine-4 Yl] -1H-pyrrole-2-carbonitrile 4- [2- (4-iodo-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2 -(3-Hydroxy-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 3,5-dimethyl-4- [2- (4-methyl-3-nitro) -Phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile 4- [2- (3-hydroxy-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl -1H-pyrrole-2-carbonitrile 4- [2- (4-fluoro-3-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2- Rubonitrile 4- [2- (4-Fluoro-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid amide [4- (2,4-dimethyl-5-nitro -1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (5-bromo-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidine -2-yl]-(3-nitro-phenyl) -amine, and [4- (5-dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-( 4-Fluoro-phenyl) -amine

The following compounds have been found to be particularly effective antiproliferative agents as a result of various cell-based assays.
[4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(3-nitro-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrole-3 -Yl) -pyrimidin-2-yl]-(4-trifluoromethyl-phenyl) -amine (3-chloro-4-iodo-phenyl)-[4- (2,4-dimethyl-1H-pyrrole-3- Yl) -pyrimidin-2-yl] -amine 3,5-dimethyl-4- [2- (3-nitro-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile 4- [2 -(4-Fluoro-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-hydroxy-phenylamino) -pyrimidin-4-yl ] -3, -Dimethyl-1H-pyrrole-2-carbonitrile 3,5-dimethyl-4- [2- (4-trifluoromethyl-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile 4- [2- (4-Iodo-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-hydroxy-phenylamino) -pyrimidine-4 -Yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 3,5-dimethyl-4- [2- (4-methyl-3-nitro-phenylamino) -pyrimidin-4-yl] -1H -Pyrrole-2-carbonitrile 4- [2- (3-iodo-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carb Boronitrile 4- [2- (4-Chloro-3-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-hydroxy- 4-Methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-fluoro-3-methyl-phenylamino) -pyrimidine-4 -Yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-fluoro-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H -Pyrrol-2-carbonitrile 4- [2- (4-dimethylamino-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4 -[2- (4-Fluoro-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid amide (4-fluoro-phenyl)-[4- (1,2 , 4-Trimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine [4- (2,4-dimethyl-5-nitro-1H-pyrrol-3-yl) -pyrimidin-2-yl ]-(4-Fluoro-phenyl) -amine N- [4- (2,4-dimethyl-5-nitro-1H-pyrrol-3-yl) -pyrimidin-2-yl] -N ', N'-dimethyl -Benzene-1,4-diamine [4- (5-bromo-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(3-nitro-phenyl) -amine [4- (5-diethylaminomethyl-2,4-di Tyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (5-dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl) ) -Pyrimidin-2-yl]-(4-fluoro-phenyl) -amine, and
[4- [2,4-Dimethyl-5- (4-methyl-piperazin-1-ylmethyl) -1H-pyrrol-3-yl] -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine

  The compounds of formula I have been found to have antiproliferative activity and are therefore useful in the treatment of cancer, leukemia and other diseases involving unregulated cell proliferation such as psoriasis and restenosis. Believed to be useful. The anti-proliferative effect within the scope of the present invention is, as defined herein, for example whole cell in vitro using any cell line of A549, HT29, Saos-2, HeLa, or MCF-7. It is clarified by the ability of inhibiting cell growth observed in a whole cell assay or by suppression of a CDK enzyme (such as CDK2 or CDK4) found in an appropriate assay. Such assays are described in more detail in Example 17, including how to perform them. By performing the above cell line assay and enzyme assay, it can be determined whether the compound is antiproliferative in light of the spirit of the present invention.

  Without wishing to be bound by theory, it is believed that the compounds of the present invention exert their antiproliferative effects independent of protein kinase C (PKC). Cyclin-dependent kinase enzyme (CDK), which has been found to be involved in cell cycle control, is inhibited by many compounds of the present invention. These CDKs include CDK2 and CDK4, especially the interaction of CDK2 and cyclin E, CDK4 and cyclin D1. Furthermore, these compounds of the present invention are believed to have the advantage of being selective for CDK enzymes involved in proliferative diseases. The term “selectivity” means that a compound has a preferential effect on enzymes involved in proliferative diseases, even if it has some inhibitory effect on other enzymes (such as PKC). means.

  The compounds of the present invention can be used in any process or stage of the cell cycle, such as nuclear membrane formation, escape from resting state (G0) in the cell cycle, progression of G1 phase, chromosome non-condensation, nuclear membrane disruption, START, DNA replication Initiation, DNA replication progression, DNA replication termination, centrosome replication, G2 phase progression, activation of functions in mitosis or meiosis, chromosome condensation, centrosome separation, microtubule nucleation, Inhibits in processes or steps such as spindle formation and function, interaction with microtubule motor proteins, separation and fragmentation of chromatids, inactivation of mitotic function, formation of contractile rings, and cytokinesis function . In particular, the compounds of the present invention have chromatin binding, replication complex formation, replication licensing, phosphorylation or other secondary modification activity, proteolysis, microtubule binding, actin binding, septin binding, microtubule organization center (microtubule It affects several gene functions, such as nucleation activity in the organizing center and binding to components in the cell cycle signaling pathway.

  Accordingly, a further embodiment of the invention relates to the use of one or more compounds of the formula I for the treatment of proliferative diseases. Such proliferative disease is preferably cancer or leukemia. Here, the term proliferative disease is used in a broad sense to include all diseases that require control of the cell cycle, such as cardiovascular diseases such as restenosis and cardiomyopathy, autoimmune diseases such as glomerulonephritis and rheumatoid arthritis. , Skin diseases such as psoriasis, anti-inflammatory diseases, antifungal diseases, antiparasitic diseases such as malaria, emphysema, and alopecia are listed. In these diseases, the compound of the present invention induces apoptosis or maintains quiescence in the desired cells as required.

  A particularly preferred embodiment of the invention relates to the use of one or more compounds of the formula I for the treatment of CDK-dependent or susceptible diseases. In CDK-dependent diseases, the activity of one or more CDK enzymes exceeds normal levels. Such a disease is preferably accompanied by an abnormal level of CDK2 and / or CDK4 activity. A CDK-sensitive disease is a disease in which an abnormal CDK level is not a primary cause, but an abnormal CDK level occurs downstream of an abnormal primary metabolism. According to such a scenario, it can be said that CDK2 and / or CDK4 are part of a sensitive metabolic pathway, and thus CDK inhibitors may be active in the treatment of the above diseases. The disease is preferably cancer or leukemia.

  As a second feature, the present invention provides a compound of formula II

[Wherein ^one of X ¹ and X ² represents NH, and the other represents CR ⁹ ;
Z represents NH, NHCO, a _{NHSO 2, NHCH 2, CH 2} , CH 2 CH 2 or CH = CH;
R ¹ , R ² , R ³ and R ⁹ are each independently a hydrogen atom, alkyl, aryl, aralkyl, heterocycle, halogeno, NO ₂ , CN, OH, alkoxy, aryloxy, NH ₂ , NH—R ′. , N- (R ′) (R ″), NH-aryl, N- (aryl) ₂ , COOH, COO-R ′, COO-aryl, CONH ₂ , CONH-R ′, CON- (R ′) ( R ″), CONH-aryl, CON- (aryl) ₂ , SO ₃ H, SO ₂ NH ₂ , CF ₃ , CO—R ′ or CO-aryl (alkyl, aryl, aralkyl and heterocyclic groups May further be substituted with one or more groups selected from halogeno, NO ₂ , CN, OH, O-methyl, NH ₂ , COOH, CONH ₂ and CF ₃ );
R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently a hydrogen atom, substituted or unsubstituted lower alkyl, halogeno, NO ₂ , CN, OH, substituted or unsubstituted alkoxy, NH ₂ , NH—R ′, N— (R ′) (R ″), COOH, COO—R ′, CONH ₂ , CONH—R ′, CON— (R ′) (R ″), SO ₃ H, SO ₂ NH ₂ and CF ₃ are shown;
R ′ and R ″ each independently represent the same or different alkyl group;
However, R ¹ and R ² are hydrogen atoms, X ¹ is NH, X ² is CH, R ³ is a hydrogen atom, and a phenyl group is
It is 3- (1,1,2,2-tetrafluoroethoxy) or 3,4,5-trimethoxy, and the case where R ^{4 to} R ⁸ other than these are hydrogen atoms is excluded. And a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating proliferative diseases.

  The term “proliferative disease” has been described above and is used interchangeably in the second aspect of the invention.

  A further feature of the present invention relates to the use of a compound of formula II for the manufacture of a medicament for the treatment of antiviral infections. Such viral infections include VZV, type I and type II HSV, and HIV. It is preferred that the compounds are used for the treatment of HIV and HIV related diseases.

  Preferred embodiments relating to further features of the invention described above are the same as the preferred embodiments described above with respect to the first feature.

  A particularly preferred embodiment is one in which one or more compounds of the present invention are administered in combination with one or more other anticancer agents. In that case, the compound of the present invention may be administered successively, simultaneously or sequentially with one or more other anticancer agents.

  As used herein, the expression “manufacturing a drug” includes, in addition to using a compound of formula I in a screening program to obtain an antiproliferative agent, or at any stage of such drug manufacturing, Includes direct use as a drug.

  The compounds of the present invention (first and second characteristics) can exist as salts or esters, particularly pharmaceutically acceptable salts or esters.

The pharmaceutically acceptable salts of the compounds of the present invention (first and second characteristics) include the appropriate acid addition or basic salts thereof. A description of suitable pharmacological salts can be found in Berge et al, J Pharm Sci, 66 , 1-19 (1977). The salt may be a strong inorganic acid such as a mineral acid (eg, sulfuric acid, phosphoric acid, or hydrohalic acid), an unsubstituted or substituted (eg, by halogen) alkane carboxylic acid having 1 to 4 carbon atoms (eg, acetic acid). ) Strong organic carboxylic acids, saturated or unsaturated dicarboxylic acids (eg; oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, tetraphthalic acid), hydroxycarboxylic acids (eg; ascorbic acid, glycol) Acid, lactic acid, malic acid, tartaric acid, or citric acid), amino acids (eg; aspartic acid or glutamic acid), benzoic acid, or unsubstituted or substituted (eg by halogen) (C ₁ -C ₄ ) alkyl- or aryl- It is formed using an organic sulfonic acid such as sulfonic acid (eg, methane- or p-toluenesulfonic acid).

Esters are formed using organic acids or alcohols / hydroxides based on the functional group to be esterified. Organic acids include unsubstituted or substituted (eg, by halogen) carboxylic acids such as alkane carboxylic acids having 1 to 12 carbon atoms (eg acetic acid), saturated or unsaturated dicarboxylic acids (eg oxalic acid, malonic acid) , Succinic acid, maleic acid, fumaric acid, phthalic acid, tetraphthalic acid), hydroxycarboxylic acid (eg; ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid), amino acid (eg; aspartic acid or glutamic acid) , Benzoic acid, or organic sulfonic acids such as unsubstituted or substituted (eg, by halogen) (C ₁ -C ₄ ) alkyl- or aryl-sulfonic acids (eg, methane- or p-toluenesulfonic acid) . Suitable hydroxides include inorganic hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide. Alcohols include unsubstituted or substituted (eg, by halogen) alkane alcohols having 1-12 carbon atoms.

  In all of the features of the invention described above, the invention appropriately includes all optical isomers and tautomers of the compounds of formula I. One skilled in the art can recognize compounds having optical properties (one or more asymmetric carbon atoms) or tautomeric characteristics. Corresponding optical isomers and / or tautomers are isolated and prepared by techniques known in the art.

  Further, the present invention relates to the compound of the present invention (first and second characteristics) or various compounds used in the present invention as various crystal forms, polymorphs, (no) hydrates. It has been established in the pharmaceutical industry that a chemical compound can be isolated from the solution used for the synthesis of such a compound in any of the above forms by slightly modifying the method of purification and / or isolation. is doing.

  The present invention further relates to a form of the compound of the present invention (first and second characteristics) or a prodrug of the compound used in the present invention. Usually, in such prodrugs, one or more suitable groups of the compound represented by Formula I are modified in such a way that the modification reverses when administered to a human or mammalian subject. A second agent can be co-administered with the prodrug to produce a retrograde in vivo, but such retrograde is usually caused by an enzyme originally possessed by the subject. Examples of such modifications include esters (eg, any of the esters described above), in which case they are reversed by esterases and the like. Other such systems are well known to those skilled in the art.

  The present invention also includes a pharmaceutical composition having the compound of the present invention (first and second characteristics). In this regard, and in particular in the treatment of humans, the compounds of the present invention (pharmaceutically acceptable salts, esters, and pharmaceutically acceptable solvates thereof) are usually contemplated even though they can be administered alone. It is administered as a mixture with pharmaceutical carriers, excipients or diluents selected in light of the route of administration and standard pharmaceutical practice.

  Accordingly, the present invention further comprises one or more compounds of formula I or II or a pharmaceutically acceptable salt or ester thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier. The present invention relates to a pharmaceutical composition.

As an example, in the pharmaceutical composition of the present invention, the compound of the present invention may be mixed with an appropriate binder, lubricant, suspending agent, coating agent, and / or solubilizer. Examples of the suitable excipients for use in the pharmaceutical compositions of the wide variety of embodiments described herein are "pharmaceutically excipient Handbook second edition (" Handbook of Pharmaceutical Excipients, 2 nd Edition "" (1994, A Wade and PJ Weller).

  The pharmaceutical composition of the present invention is oral, vaginal, rectal, parenteral, intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial, subcutaneous, intradermal, intravenous, nasal, buccal, Or it can administer from each sublingual route.

  For oral administration, compressed tablets, pills, tablets, gells, drops, and capsules are particularly used. These compositions preferably contain 1-250 mg of active ingredient per dose, more preferably 10-100 mg.

  Other dosage forms include solutions or emulsions that are injected intravenously, intraarterially, intrathecally, subcutaneously, intradermally, intraperitoneally, or intramuscularly, and are sterile or sterilizable solutions. Prepared from The pharmaceutical composition of the present invention may also be in the form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or powders.

  Another method for transdermal administration is to use a skin patch. For example, the active ingredient can be contained in a cream comprising a polyethylene glycol aqueous emulsion or liquid paraffin. In addition, the active ingredient can be contained in an ointment composed of white wax or a white soft paraffin base in a concentration range of 1 to 10% by weight together with a stabilizer and a preservative as necessary.

  The injection dosage form can contain 10 to 1000 mg of active ingredient per dose, and preferably 10 to 250 mg.

  The composition is formulated in unit dosage form, ie, containing a single unit dose, or in separate portions containing a single unit dose divided into multiple or subunits.

  A person of ordinary skill in the art can readily determine the appropriate dosage to administer to a subject for any one of the compositions of the present invention without undue experimentation. Usually, the physician will determine the optimum actual dosage for an individual patient, which will vary with the age, weight and responsiveness of the individual patient. The dosage disclosed herein is an average case. Depending on the individual case, naturally higher doses or lower doses may be successful, which are also within the scope of the present invention.

  As an exemplary embodiment, for treatment of malignant diseases, a daily dose of 10 to 150 mg is administered to a patient in one or more divided doses.

  The pharmaceutical composition of the present invention may further contain one or more anticancer agents such as existing anticancer agents that are commercially available.

  In general, anticancer agents are more effective when used in combination. In particular, combination therapy is desirable to avoid duplication of major toxicities, mechanisms of action and resistance mechanisms. Furthermore, for most drugs it is desirable to administer the maximum tolerated dose at the minimum dosing interval. The main benefits gained by combining chemotherapeutic drugs are that biochemical interactions may facilitate additional effects or possible synergies, and the first chemotherapy with a single drug It may be possible to attenuate the emergence of resistance in early tumor cells that respond to. An example of using biochemical interactions when selecting drug combinations is that leucovorin enhances the binding of the active intracellular metabolite of 5-fluorouracil to its target thymidylate synthase As a result, the cytotoxic effect is enhanced.

  Currently, a large number of drug combinations are used to treat cancer and leukemia. A broader overview in the medical setting is described in "Oncologic Therapies" (E.E. Vokes and HM Golomb, Springer).

  By examining the growth inhibitory activity of a test compound in conjunction with an agent that is recognized or considered effective in the initial treatment of a particular cancer or in a cell line derived from that cancer, an effective combination can be obtained. It is suggested. The above method can also be adopted when determining the order of drug administration, that is, before, simultaneously with, or after delivery of one drug. Such a regimen is characteristic of all cyclic actives identified in the present invention.

  The compound (I) of the present invention can be synthesized by, for example, Traube synthesis method (AR Katritzky, I. Taher, Can. J. Chem. 1986, 64, 2087 and references cited therein), that is, as shown in Scheme 1, , 3-dicarbonyl compound 1 or acrylic acid 2 or 3 and amidine 4 can be synthesized.

Further, dicarbonyl compounds 1 can be prepared by a variety of methods known in the art (J. March, In: Advanced Organic Chemistry:. Reactions, Mechanism, and Structure, 4 th Ed, John Wiley & Sons, Inc. , New York, 1992, p. 1283). Particularly preferred acrylic acids 2 and 3 for the purposes of the present invention are obtained by condensation of heterocyclic methyl ketone 5 with tert-butoxybis (dimethylamino) methane 6 (Scheme 2).

The diamino compound 4 in Scheme 1 becomes amidine 4a or guanidine 4b depending on the definition of Z in general formula I. Amidines (HN = CRNH ₂ ) are obtained from readily available amine precursors, for example by condensation with ketene imines or by adding ammonia to the appropriate nitrile or imidic acid. Guanidine 4b can be synthesized by a number of methods known in the art. The most useful route in view of the purpose of the present invention is amination of cyanamide 8 with aniline 9 (Scheme 3).

When 5 in Scheme 2 is pyrrole, two systems can be employed (see Scheme 4). That is, the acetyl group used for the production of pyrimidine precursors 2 and 3 is pyrrole 3-position (5: X ¹ = CR ⁹ , X ² = NH; structure 5b) or pyrrole 2-position (X ¹ = NH, X ² = CR ⁹ ; Two systems in any of structures 5c) can be used.

In either case, the pyrrole ring can be synthesized using techniques known in the art. Particularly suitable methods are, (as an example, JA Joule, GF Smith, Heterocyclic Chemistry, 2 nd Ed., Van Nostrand Reinhold (UK) Co. Ltd., 1978, pp. See 213-215) Knorr synthesis method by modified It is. In the pyrrol-3-yl system, the activated (that is, R ¹ = COOEt, CN, etc.) carbonyl compound 10 is first nitrated. Reactive α-aminocarbonyl intermediate 13 is formed by condensing oxime 11 obtained with dicarbonyl compound 12 in the presence of, for example, zinc acetate or aqueous dithionate. The resulting R ¹ substituent in 3-acetylpyrrole 5b (eg; COOEt, CN) can be further transformed directly or in Intermediate 2 or 3, or in the pyrrolpyrimidine product (Formula I). For example, decarboxylation (R ¹ = COOEt) yields a product where R ¹ = H, and oxidation (R ¹ = CN) yields a product where R ¹ = CONH ₂ .

Furthermore, products in which R ¹ = H can be converted into various derivatives, in particular by electrophilic substitution. Therefore, a derivative in which R ¹ is a group such as halogen, nitro, amino, alkyl, alkylamino and the like can be easily obtained. A similar situation occurs in the case of the pyrrol-2-yl system, but in this system, it is necessary that an active group is present in the carbonyl component 15 (eg, R ⁹ = COOEt, CN, etc.). This is condensed with oxime 16 (derived from dicarbonyl compound 14) to form intermediate 17. The R ⁹ substituent in the product 5c or derivative can be converted in the same manner as the R ¹ group in the pyrrol-3-yl system described above.

  Alternatively, compounds of general formula I can also be obtained directly from the appropriate pyrimidine precursors, for example from 2,4-disubstituted (halogen, amine, etc.) pyrimidines by successive substitution reactions.

  The invention will now be described by way of example and with reference to the following figures.

Abbreviation LC-MS (liquid chromatography mass spectrum analysis),
NMR (nuclear magnetic resonance spectroscopy),
r. t. (room temperature),
PE (petroleum ether) (40-60 ° C boiling fraction),
DMSO (dimethyl sulfoxide)

General NMR spectra were recorded using a Bruker DPX-300 instrument. Chemical shifts were recorded in ppm (δ) from tetramethylsilane. EM Kieselgel 60 (0.040-0.063 mm) was used for flash column chromatography. The melting point (Mp) was measured with a LEICA testo-720 electric thermometer and was not calibrated. Compound numbers are shown in parentheses as needed.

3-Dimethylamino-1- (2,4-dimethyl-1H-pyrrol-3-yl) -propenone

1- (2,4-dimethyl-1H-pyrrol-3-yl) -ethanone (2 g, 15 mmol) added to 5 mL of 1,1-bis-dimethylamino-3,3-dimethyl-butan-2-one Was heated at 100 ° C. for 22 hours. The reaction mixture precipitate was slurried in EtOAc / PE under cooling. The crude product was filtered, washed with EtOAc / PE, and dried in vacuo to give 2.6 g of the title compound as a purple solid.
¹ H-NMR (CDCl ₃ ) δ: 2.25 (s, 6H, CH ₃ ), 2.45 (s, 6H, CH ₃ ), 5.46 (d, 1H, J = 12.6 Hz, CH) 6.35 (s, 1H, pyrrole-H), 7.63 (d, 1H, J = 12.6 Hz, CH).

[4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine (Compound 1)
To 5 mL of 2-methoxyethanol, 0.19 g (1 mmol) of 3-dimethylamino-1- (2,4-dimethyl-1H-pyrrol-3-yl) -propenone and 0.44 g (2 mmol) of 4-fluorophenylguanidine nitrate ) Was added to 40 mg NaOH. The reaction mixture was heated at 100-120 ° C. for 6 hours under a nitrogen atmosphere. The solvent was evaporated to dryness and the residue was purified by flash chromatography (1: 2 EtOAc: PE). Recrystallization from EtOAc / PE gave 174 mg (62%) of the title compound as brown crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.21 (s, 3H, CH ₃ ), 2.43 (s, 3H, CH ₃ ), 6.33 (s, 1H, pyrrole-H), 6.73 (D, 1H, J = 5.3 Hz, pyrimidinyl-H), 7.00 (m, 2H, Ph-H), 7.79 (m, 2H, Ph-H), 8.28 (d, 1H, J = 5.3 Hz, pyrimidinyl-H), 9.16 (s, 1H, NH), 10.59 (s, 1H, NH).

  The following compounds were prepared in the same manner as above.

[4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(3-nitro-phenyl) -amine (Compound 2)
Yellow-orange solid. M.M. p. 197-199 ° C., LC-MS: m / z = 310 (M + 1). C ₁₆ H ₁₅ N ₅ O ₂ requires C, 62.12; H, 4.89; N, 22.64; found C, 62.61; H, 4.99; N, 22.20. ¹ H-NMR (CDCl ₃ ) δ: 2.71 (d, 6H, CH ₃ ), 7.05 (d, 1H, J = 5.3 Hz, pyrimidinyl-H), 7.47 (m, 2H, Ph -H), 7.78 (m, 1H, Ph-H), 7.81 (s, 1H, Ar-H), 8.07 (m, 1H, Ph-H), 8.51 (d, 1H) , J = 5.3 Hz, pyrimidinyl-H), 8.99 (br.s, 1H, NH), 9.91 (br.s, 1H, NH).

[4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-iodo-phenyl) -amine (Compound 3)
¹ H-NMR (CDCl ₃ ) δ: 2.26 (s, 3 H, CH ₃ ), 2.48 (s, 3 H, CH ₃ ), 6.80 (d, 1 H, J = 5.3 Hz, pyrimidinyl- H), 7.47 (m, 2H, Ph-H), 7.57 (m, 2H, Ph-H), 7.23 (s, 1H, pyrrole-H), 8.32 (d, 1H, J = 5.3 Hz, pyrimidinyl-H).

(3,4-Difluoro-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (compound 4)
¹ H-NMR (CDCl ₃ ) δ: 2.23 (s, 3H, CH ₃ ), 2.46 (s, 3H, CH ₃ ), 6.42 (m, 1H, pyrrole-H), 6.77 (D, 1H, J = 5.3 Hz, pyrimidinyl-H), 7.11 (m, 1H, Ph-H), 7.41 (m, 1H, Ph-H), 8.05 (m, 1H, Ph-H), 8.29 (d, 1H, J = 5.3 Hz, pyrimidinyl-H), 9.21 (s, 1H, Ph-H), 10.46 (br.s, 1H, NH).

(4-Chloro-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (Compound 5)
M.M. p. ^{219-223 ℃, MS: [M +} H] + = 299.4 (C 16 H 15 ClN 4 requires 298.8). ¹ H-NMR (DMSO-d ₆ ) δ: 2.19 (s, 3H, CH ₃ ), 2.42 (s, 3H, CH ₃ ), 6.48 (s, 1H, pyrrolyl-H), 6 .82 (d, 1H, J = 5.3 Hz, pyrimidinyl-H), 7.31 (d, 2H, J = 8.7 Hz, Ph-H), 7.84 (d, 2H, J = 8.7 Hz) , Ph-H), 8.34 (d, 1H, J = 5.3 Hz, pyrimidinyl-H), 9.45 (s, 1H, Ph-H), 10.72 (br.s, 1H, NH) .

(3,5-Difluoro-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (Compound 6)
M.M. p. 153.3-156.8 ° C., MS: [M + H] ⁺ = 303.6 (C ₁₆ H ₁₄ F ₂ N ₄ requires 300.3). ¹ H-NMR (CD ₃ OD) δ: 2.25 (s, 3H, CH ₃ ), 2.47 (s, 3H, CH ₃ ), 6.42 to 6.48 (m, 2H, pyrrolyl-H And Ph-H), 6.80 (d, 1H, J = 5.5 Hz, pyrimidinyl-H), 7.44-7.48 (m, 2H, Ph-H), 8.31 (d, 1H, J = 5.5 Hz, pyrimidinyl-H).

4- [4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-ylamino] -phenol (Compound 7)
M.M. p. 189.5-193.4 ° C., MS: [M + H] ⁺ = 281.9 (C ₁₆ H ₁₆ N ₄ O requires 280.3). ¹ H-NMR (CD ₃ OD) δ: 2.23 (s, 3H, CH ₃ ), 2.43 (s, 3H, CH ₃ ), 6.44 (s, 1H, pyrrolyl-H), 6. 75-6.78 (m, 3H, pyrimidinyl-H and Ph-H), 7.39 (d, 2H, J = 8.8 Hz, Ph-H), 8.17 (d, 1H, J = 5. 3 Hz, pyrimidinyl-H).

3- [4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-ylamino] -phenol (Compound 8)
M.M. p. 169.0-174.6 ° C., MS: [M + H] ⁺ = 281.3 (C ₁₆ H ₁₆ N ₄ O requires 280.3). ¹ H-NMR (CD ₃ OD) δ: 2.26 (s, 3H, CH ₃ ), 2.47 (s, 3H, CH ₃ ), 6.44 to 6.48 (m, 2H, pyrrolyl-H , Ph-H), 6.84 (d, 1H, J = 5.4 Hz, pyrimidinyl-H), 7.05 to 7.10 (m, 2H, Ph-H), 7.32 (m, 1H, Ph-H), 8.25 (d, 1H, J = 5.3 Hz, pyrimidinyl-H).

(2,4-Difluoro-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (Compound 9)
M.M. p. ^{219-220 ℃, MS: [M +} H] + = 302.6 (C 16 H 14 F 2 N 2 requires 300.3). ¹ H-NMR (DMSO-d ₆ ) δ: 2.10 (s, 3H, CH ₃ ), 2.36 (s, 3H, CH ₃ ), 6.43 (s, 1H, pyrrolyl-H), 6 .77 (d, 1H, J = 5.3 Hz, pyrimidinyl-H), 7.06 (m, 1H, Ph-H), 7.27 (m, 1H, Ph-H), 7.66 (m, 1H, Ph-H), 8.25 (d, 1H, J = 5.3 Hz, pyrimidinyl-H), 8.71 (s, 1H, Ph-H), 10.70 (br.s, 1H, NH) ).

(2,4-Dichloro-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (Compound 10)
M.M. p. 158.5-159.7 ° C., MS: [M + H] ⁺ = 335.4 (C ₁₆ H ₁₄ Cl ₂ N ₄ requires 333.2). ¹ H-NMR (DMSO-d ₆ ) δ: 2.18 (s, 3H, CH ₃ ), 2.38 (s, 3H, CH ₃ ), 6.51 (s, 1H, pyrrolyl-H), 6 .90 (d, 1H, J = 5.5 Hz, pyrimidinyl-H), 7.46 (m, 1H, Ph-H), 7.71 (m, 1H, Ph-H), 8.05 (m, 1H, Ph-H), 8.36 (d, 1H, J = 5.3 Hz, pyrimidinyl-H), 8.49 (s, 1H, Ph-H), 10.80 (br.s, 1H, NH) ).

(4-Chloro-3-trifluoromethyl-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (Compound 11)
M.M. p. 187.7-190.7 ° C., MS: [M + H] ⁺ = 368.6 (C ₁₇ H ₁₄ ClF ₃ N ₄ requires 366.8). ¹ H-NMR (DMSO-d ₆ ) δ: 2.19 (s, 3H, CH ₃ ), 2.42 (s, 3H, CH ₃ ), 6.50 (s, 1H, pyrrolyl-H), 6 .89 (d, 1H, J = 5.3 Hz, pyrimidinyl-H), 7.61 (m, 1H, Ph-H), 8.08 (m, 1H, Ph-H), 8.39-8. 42 (m, 2H, Ph-H and pyrimidinyl-H), 9.79 (s, 1H), 10.80 (br.s, 1H, NH).

[4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-trifluoromethyl-phenyl) -amine (Compound 12)
M.M. p. 165.6-167.9 ° C., MS: [M + H] ⁺ = 332.9 (C ₁₇ H ₁₅ F ₃ N ₄ requires 332.3). ¹ H-NMR (DMSO-d ₆ ) δ: 2.26 (s, 3H, CH ₃ ), 2.49 (s, 3H, CH ₃ ), 6.56 (s, 1H, pyrrolyl-H), 6 .94 (d, 1H, J = 5.3 Hz, pyrimidinyl-H), 7.67 (d, 2H, J = 8.5 Hz, Ph-H), 8.09 (d, 2H, J = 8.5 Hz) , Ph-H), 8.45 (d, 1H, J = 5.3 Hz, pyrimidinyl-H), 9.82 (s, 1H, NH).

[4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(3-trifluoromethyl-phenyl) -amine (Compound 13)
M.M. p. 152.7-154.3 ° C., MS: [M + H] ⁺ = 332.6 (C ₁₇ H ₁₅ F ₃ N ₄ requires 332.3). ¹ H-NMR (DMSO-d ₆ ) δ: 2.26 (s, 3H, CH ₃ ), 2.48 (s, 3H, CH ₃ ), 6.56 (s, 1H, pyrrolyl-H), 6 .92 (d, 1H, J = 5.3 Hz, pyrimidinyl-H), 7.29 (m, 1H, Ph-H), 7.55 (m, 1H, Ph-H), 8.03 (m, 1H, Ph-H), 8.42-7.45 (m, 2H, pyrimidinyl-H and Ph-H), 9.73 (s, 1H, NH), 10.83 (br.s, 1H, NH) ).

(3-Chloro-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (Compound 14)
M.M. p. ^{140.4-144.2 ℃, MS: [M +} H] + = 299.5 (C 16 H 15 ClN 4 requires 298.8). ¹ H-NMR (DMSO-d ₆ ) δ: 2.21 (s, 3H, CH ₃ ), 2.44 (s, 3H, CH ₃ ), 6.51 (s, 1H, pyrrolyl-H), 6 .85 (d, 1H, J = 5.3 Hz, pyrimidinyl-H), 6.94 (d, 1H, J = 7.6 Hz, Ph-H), 7.28 (t, 1H, J = 8.1 Hz) , Ph-H), 7.61 (d, 1H, J = 8.2 Hz, Ph-H), 8.19 (s, 1H, Ph-H), 8.37 (d, 1H, J = 5. 3 Hz, pyrimidinyl-H), 9.55 (s, 1 H, NH), 10.78 (br. S, 1 H, NH).

N- [4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -N ′, N′-dimethyl-benzene-1,4-diamine (Compound 15)
M.M. p. ^{179.9-182.1 ℃, MS: [M +} H] + = 307.3 (C 18 H 21 N 5 requires 307.4). ¹ H-NMR (CDCl ₃ ) δ: 2.25 (s, 3H, CH ₃ ), 2.46 (s, 3H, CH ₃ ), 2.91 (s, 6H, CH ₃ ), 6.46 ( s, 1H, pyrrolyl-H), 6.70 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 6.78 (dd, 2H, J = 6.8, 2.2 Hz, Ph-H) 6.79 (br.s, 1H, NH), 7.45 (dd, 2H, J = 6.8, 2.2 Hz, Ph-H), 7.80 (br.s, 1H, NH), 8.28 (d, 1H, J = 5.1 Hz, pyrimidinyl-H).

(3-Chloro-4-iodo-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (Compound 16)
M.M. p. ^{185.0-187.4 ℃, MS: [M +} H] + = 423.9 (C 16 H 14 ClIN 4 requires 424.7). ¹ H-NMR (DMSO-d ₆ ) δ: 2.18 (s, 3H, CH ₃ ), 2.41 (s, 3H, CH ₃ ), 6.48 (s, 1H, pyrrolyl-H), 6 .84 (d, 1H, J = 5.4 Hz, pyrimidinyl-H), 7.40 (dd, 1H, J = 8.8, 2.4 Hz, Ph-H), 7.75 (d, 1H, J = 8.8 Hz, Ph-H), 8.34 (m, 1H, Ph-H), 8.36 (d, 1H, J = 5.4 Hz, pyrimidinyl-H), 9.61 (s, 1H, NH), 10.75 (s, 1H, NH).

[4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(3-fluoro-4-iodo-phenyl) -amine (Compound 17)
M.M. p. ^{200-202 ℃, MS: [M +} H] + = 407.4 (C 16 H 14 FIN 4 requires 408.2). ¹ H-NMR (DMSO-d ₆ ) δ: 2.18 (s, 3H, CH ₃ ), 2.40 (s, 3H, CH ₃ ), 6.48 (s, 1H, pyrrolyl-H), 6 .84 (d, 1H, J = 5.4 Hz, pyrimidinyl-H), 7.35 (m, 1H, Ph-H), 7.64 (t, 1H, J = 8.0 Hz, Ph-H), 8.02 (dd, 1H, J = 12.0, 2.2 Hz, Ph-H), 8.36 (d, 1H, J = 5.4 Hz, pyrimidinyl-H), 9.65 (s, 1H, NH), 10.75 (s, 1H, NH).

4- (3-Dimethylamino-acryloyl) -3,5-dimethyl-1H-pyrrole-2-carbonitrile

10 mL (94 mmol) of ethyl cyanoacetate was dissolved in 20 mL of AcOH, and the solution was cooled to −10 ° C. (MeOH ice bath). A solution prepared by dissolving 6.5 g (94 mmol) of NaNO _{2 in} 10 mL of water was added dropwise to the above for 40 minutes so that the internal temperature was kept below 0 ° C. After completion of the addition, the reaction mixture was stirred for 1 hour under cooling. The reaction mixture was then warmed to room temperature and stirred for an additional 3 hours. The mixture was diluted with 50 mL acetic acid and 50 mL water. Pentane-2,4-dione 10.6 mL (103 mmol) was added to the above mixture and heated to 75 ° C. To this reaction mixture, 6.9 g (105 mmol) of zinc powder was added in small portions over 30 minutes at a rate that kept the internal temperature below 90 ° C. The reaction mixture was heated for an additional 30 minutes and then poured into 1 mL of water. From this reaction mixture, 3.67 g of 3,5-dimethyl-1H-pyrrole-2-carbonitrile was collected by filtration as an off-white solid. The filtrate was extracted with EtOAc (3 × 500 mL). The organic extracts were combined, washed and dried (MgSO ₄ ). The solvent was evaporated to give a brown oil that was purified by chromatography (100 g SiO ₂ , heptane / EtOAc 4: 1) to give 4.41 g (72% overall yield) of the product as a pale yellow solid.

1.2 g (10 mmol) of 3,5-dimethyl-1H-pyrrole-2-carbonitrile was dissolved in 15 mL of anhydrous 1,2-dichloroethane, and 2.93 g (22 mmol) of AlCl ₃ was added in portions. The reactor was purged with nitrogen and cooled by immersion in an ice bath. After 0.71 mL (10 mmol) of AcCl was added dropwise, the mixture was stirred under cooling for 1 hour and further at room temperature for 3 hours. The reaction mixture was quenched by careful addition of 2M aqueous hydrochloric acid. The mixture was adjusted to about pH 6 by adding NaHCO ₃ . The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 100 mL). The organic layers were combined, washed with water, then brine, dried (MgSO ₄ ) and filtered. The solvent was evaporated to give 1.42 g (88%) of 4-acetyl-3,5-dimethyl-1H-pyrrole-2-carbonitrile as a light brown solid.
¹ H-NMR (CDCl ₃ ) δ: 2.44 (s, 3H, CH ₃ ), 2.45 (s, 3H, CH ₃ ), 2.54 (s, 3H, CH ₃ ), 8.75 ( br.s, 1H, NH).

4-acetyl-3,5-dimethyl-1H-pyrrole-2-carbonitrile (1.38 g (8.51 mmol) was converted to 1,1-bis-dimethylamino-3,3-dimethyl-butan-2-one 1 Suspended in 3 mL and heated for 42 hours at 75 ° C. The solvent of the reaction mixture was evaporated to dryness and the residue was purified by SiO ₂ chromatography (heptane / EtOAc) to give the title compound 1. 2 g (65%) were obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 2.21 (s, 3H, CH ₃ ), 2.31 (s, 3H, CH ₃ ), 3.32 (s, 6H, CH ₃ ), 5. 22 (d, 1H, J = 12.4 Hz, CH), 7.47 (d, 1H, J = 12.4 Hz, CH), 11.96 (br.s, 1H, NH).

3,5-Dimethyl-4- [2- (3-nitro-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile (Compound 31)

4- (3-dimethylamino-acryloyl) -3,5-dimethyl-1H-pyrrole-2-carbonitrile 0.22 g (1.0 mmol) and 3-nitrophenylguanidine nitrate 0.36 g (1.5 mmol) To 2 mL of 2-methoxyethanol mixed solution, 138 mg (1.0 mmol) of K ₂ CO ₃ was added. The reaction mixture was heated at 120 ° C. for 18 hours under a nitrogen atmosphere. The solvent was evaporated to dryness and the residue was purified by flash chromatography (EtOAc / heptane 1: 2) to give the title compound as a pale yellow solid.
M.M. p. 258-259 ° C., MS: [M + H] ⁺ = 336.1 (C ₁₇ H ₁₄ N ₆ O ₂ requires 334.3). ¹ H-NMR (CD ₃ OD) δ: 2.39 (s, 3H, CH ₃ ), 2.49 (s, 3H, CH ₃ ), 6.94 (d, 1H, J = 5.1 Hz, pyrimidinyl -H), 7.50 (t, 1H, J = 8.3 Hz, Ph-H), 7.81 (m, 1H, Ph-H), 7.94 (m, 1H, Ph-H), 8 .45 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 8.94 (t, 1H, J = 2.2 Hz, Ph-H).

  The following compounds were prepared by the same method as above.

4- [2- (4-Fluoro-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile (Compound 32)
^{MS: [M + H] +} = 307.7 (C 17 H 14 FN 5 requires 307.3). ¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (s, 3H, CH ₃ ), 2.40 (s, 3H, CH ₃ ), 6.84 (d, 1H, J = 5.0 Hz, Pyrimidinyl-H), 7.00 (m, 2H, Ph-H), 7.73 (m, 2H, Ph-H), 8.40 (d, 1H, J = 5.5 Hz, pyrimidinyl-H), 9.46 (s, 1H, NH), 12.19 (br.s, 1H, NH).

4- [2- (4-Hydroxy-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile (Compound 33)
M.M. p. ^{272-276 ℃, MS: [M +} H] + = 305.8 (C 17 H 15 N 5 O requires 305.3). ¹ H-NMR (CD ₃ OD) δ: 2.33 (s, 3H, CH ₃ ), 2.41 (s, 3H, CH ₃ ), 6.74-6.56 (m, 3H, pyrimidinyl-H / Ph-H), 7.36 (d, 2H, J = 8.5 Hz, Ph-H), 8.25 (d, 1H, J = 5.4 Hz, pyrimidinyl-H).

3,5-Dimethyl-4- [2- (4-trifluoromethyl-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile (Compound 34)
M.M. p. 195.6-198.9 ° C., MS: [M + H] ⁺ = 357.7 (C ₁₈ H ₁₄ F ₃ N ₅ requires 357.3). ¹ H-NMR (CDCl ₃ ) δ: 2.33 (s, 3 H, CH ₃ ), 2.44 (s, 3 H, CH ₃ ), 6.75 (d, 1 H, J = 5.1 Hz, pyrimidinyl- H), 7.20 (br.s, 1H, NH), 7.50 (d, 2H, J = 8.8 Hz, Ph-H), 7.71 (d, 2H, J = 8.8 Hz, Ph) -H), 8.39 (d, 1H, J = 5.1 Hz, pyrimidinyl), 8.40 (br.s, 1H, NH).

4- [2- (4-Iodo-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile (Compound 35)
M.M. p. 178.3-181.2 ° C., MS: [M + H] ⁺ = 416.6 (C ₁₈ H ₁₄ IN ₅ requires 415.2). ¹ H-NMR (CDCl ₃ ) δ: 2.39 (s, 3 H, CH ₃ ), 2.49 (s, 3 H, CH ₃ ), 6.76 (d, 1 H, J = 5.1 Hz, pyrimidinyl- H), 7.10 (br, s, 1H, NH), 7.44 (d, 2H, J = 8.8 Hz, Ph-H), 7.61 (d, 2H, J = 8.8 Hz, Ph) -H), 8.42 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 8.45 (br.s, 1H, NH).

4- [2- (3-Hydroxy-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile (Compound 36)
M.M. p. ^{247-250 ℃, MS: [M +} H] + = 305.8 (C 17 H 15 N 5 O requires 305.3). ¹ H-NMR (DMSO-d ₆ ) δ: 2.31 (s, 3H, CH ₃ ), 2.41 (s, 3H, CH ₃ ), 6.33 (m, 1H, Ph—H), 6 .82 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 7.01 (t, 1H, J = 8.1 Hz, Ph-H), 7.11 (m, 1H, Ph-H), 7.33 (t, 1H, J = 2.1 Hz, Ph-H), 8.40 (d, 1H, J = 5.4 Hz, pyrimidinyl-H), 9.18 (s, 1H), 9.30 (S, 1H), 12.20 (br.s, 1H, NH).

3,5-Dimethyl-4- [2- (4-methyl-3-nitro-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile (Compound 37)
M.M. p. 233-237 ° C., MS: [M + H] ⁺ = 350.0 (C ₁₈ H ₁₆ N ₆ O ₂ requires 348.6). ¹ H-NMR (DMSO-d ₆ ) δ: 2.31 (s, 3H, CH ₃ ), 2.42 (s, 3H, CH ₃ ), 2.44 (s, 3H, CH ₃ ), 6. 92 (d, 1H, J = 5.4 Hz, pyrimidinyl-H), 7.39 (d, 1H, J = 8.5 Hz, Ph-H), 7.87 (dd, 1H, J = 8.1) 1.7 Hz, Ph-H), 8.48 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 8.63 (d, 1H, J = 1.7 Hz, Ph-H), 9.87. (S, 1H, NH), 12.21 (br.s, 1H, NH).

4- [2- (3-Iodo-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile (Compound 38)
M.M. p. 189.5-191.7 ° C., MS: [M + H] ⁺ = 431.5 (C ₁₈ H ₁₆ IN ₅ requires 429.6). ¹ H-NMR (DMSO-d ₆ ) δ: 2.29 (s, 3H, CH ₃ ), 2.32 (s, 3H, CH ₃ ), 2.43 (s, 3H, CH ₃ ), 6. 85 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 7.20 (d, 1H, J = 8.1 Hz, Ph-H), 7.57 (m, 1H, Ph-H), 8 .41-8.43 (m, 2H, Ph-H, pyrimidinyl-H), 9.48 (s, 1H, NH), 12.20 (br.s, 1H, NH).

4- [2- (4-Chloro-3-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile (Compound 39)
M.M. p. ^{194.2-197.9 ℃, MS: [M +} H] + = 338.0 (C 18 H 16 ClN 5 requires 337.8). ¹ H-NMR (DMSO-d ₆ ) δ: 2.27 (s, 3H, CH ₃ ), 2.31 (s, 3H, CH ₃ ), 2.41 (s, 3H, CH ₃ ), 6. 86 (d, 1H, J = 5.4 Hz, pyrimidinyl-H), 7.28 (d, 1H, J = 8.5 Hz, Ph-H), 7.61 (dd, 1H, J = 8.8, 2.4 Hz, Ph-H), 7.73 (d, 1H, J = 2.7 Hz, Ph-H), 8.43 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 9.51. (S, 1H, NH), 12.21 (br.s, 1H, NH).

4- [2- (3-Hydroxy-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile (Compound 40)
M.M. p. 221-225 ° C, MS: [M + H] ⁺ = 320.9 (C ₁₈ H ₁₇ N ₅ O requires 319.4). ¹ H-NMR (DMSO-d ₆ ) δ: 2.03 (s, 3H, CH ₃ ), 2.29 (s, 3H, CH ₃ ), 2.40 (s, 3H, CH ₃ ), 6. 78 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 6.89 (d, 1H, J = 8.1 Hz, Ph-H), 7.02 (dd, 1H, J = 8.3) 1.7 Hz, Ph-H), 7.29 (d, 1 H, J = 0.7 Hz, Ph-H), 8.37 (d, 1 H, J = 4.9 Hz, pyrimidinyl-H), 9.08 (S, 1H), 9.20 (s, 1H), 12.17 (br.s, 1H, NH).

4- [2- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile (Compound 41)
M.M. p. 161.3-164.1 ° C., MS: [M + H] ⁺ = 321.6 (C ₁₈ H ₁₆ FN ₅ requires 321.4). ¹ H-NMR (DMSO-d ₆ ) δ: 2.19 (s, 3H, CH ₃ ), 2.30 (s, 3H, CH ₃ ), 2.42 (s, 3H, CH ₃ ), 6. 82 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 7.03 (t, 1H, J = 9.3 Hz, Ph-H), 7.53 (m, 1H, Ph-H), 7 .61 (dd, 1H, J = 7.1, 2.4 Hz, Ph-H), 8.39 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 9.36 (s, 1H, NH) ), 12.20 (br.s, 1H, NH).

4- [2- (3-Fluoro-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile (Compound 42)
M.M. p. ^{177.7-179.9 ℃, MS: [M +} H] + = 322.5 (C 18 H 16 FN 5 requires 321.3). ¹ H-NMR (DMSO-d ₆ ) δ: 2.15 (s, 3H, CH ₃ ), 2.30 (s, 3H, CH ₃ ), 2.43 (s, 3H, CH ₃ ), 6. 86 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 7.13 (t, 1H, J = 9.0 Hz, Ph-H), 7.36 (dd, 1H, J = 8.1) 1.7 Hz, Ph-H), 7.75 (dd, 1 H, J = 12.9, 1.5 Hz, Ph-H), 8.43 (d, 1 H, J = 5.4 Hz, pyrimidinyl-H) , 9.56 (s, 1H, NH), 12.21 (br.s, 1H, NH).

4- [2- (4-Dimethylamino-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile (Compound 43)
M.M. p. 190.6-193.7 ° C., MS: [M + H] ⁺ = 334.7 (C ₁₉ H ₂₀ N ₆ requires 332.4). ¹ H-NMR (CDCl ₃ ) δ: 2.36 (s, 3H, CH ₃ ), 2.46 (s, 3H, CH ₃ ), 2.94 (br. S, 6H, CH ₃ ), 6. 66 (d, 1H, J = 5.6 Hz, pyrimidinyl-H), 6.79-6.80 (m, 2H, Ph-H), 7.05 (br.s, 1H, NH), 7.40. ~ 7.43 (m, 2H, Ph-H), 8.34 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 8.52 (br.s, 1H, NH).

4- (3-Dimethylamino-acryloyl) -3,5-dimethyl-1H-pyrrole-2-carboxylic acid amide

1.1 g (10 mmol) of 1- (2,4-dimethyl-1H-pyrrol-3-yl) -ethanone was partially dissolved in 2M ammonia MeOH solution, and 10 mL of H ₂ O ₂ 27% w / w aqueous solution was added inside the solution. The dropwise addition was performed for 40 minutes at a rate that kept the temperature below 30 ° C. The mixture was stirred at room temperature for 18 hours. The resulting suspended white solid was filtered and recrystallized with EtOAc to give 1.06 g of 4-acetyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid amide. 1,1-bis-dimethylamino-3,3-dimethyl-butane-in a flask substituted with 720 mg (4 mmol) of the obtained 4-acetyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid amide Suspended in 2 mL (9.6 mmol) of 2-one and heated at 75 ° C. for 48 hours. The crude mixture was cooled and purified by SiO ₂ chromatography (EtOAc / MeOH gradient elution). The title compound, 449 mg, was obtained as a pale yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (s, 3H, CH ₃ ), 2.46 (s, 3H, CH ₃ ), 2.90 (br.s, 2H, NH), 3 .09 (s, 3H, CH ₃ ), 3.13 (s, 3H, CH ₃ ), 5.23 (d, 1H, J = 12.4 Hz, CH), 7.38 (d, 1H, J = 12.7 Hz, CH), 10.97 (br.s, 1H, NH).

4- [2- (4-Fluoro-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid amide (Compound 44)
4- (3-Dimethylamino-acryloyl) -3,5-dimethyl-1H-pyrrole-2-carboxylic acid amide 100 mg (0.43 mmol), 4-fluorophenylguanidine nitrate 139 mg (0.65 mmol), and K ₂ CO ₃ 94 mg (0.68 mmol) was partially dissolved in 5 mL of 2-methoxyethanol and heated at 120 ° C. for 18 hours. The mixture was concentrated in vacuo and purified by SiO ₂ chromatography (EtOAc / MeOH gradient elution). This product was triturated in iPr ₂ O to give 31 mg of the title compound as a pale yellow solid.
M.M. p. 93.5-96.8 ° C., MS: [M + H] ⁺ = 326.9 (C ₁₇ H ₁₆ FN ₅ O requires 325.3). ¹ H-NMR (DMSO-d ₆ ) δ: 2.36 (s, 3H, CH ₃ ), 2.39 (s, 3H, CH ₃ ), 6.79 (d, 1H, J = 5.4 Hz, Pyrimidinyl-H), 6.92 (br.s, 2H, NH), 7.07 (t, 2H, J = 8.5 Hz, Ph-H), 7.76-7.78 (m, 2H, Ph -H), 8.36 (d, 1H, J = 5.4 Hz, pyrimidinyl-H), 9.41 (s, 1H, NH), 11.24 (br.s, 1H, NH).

3-Dimethylamino-1- (3,5-dimethyl-1H-pyrrol-2-yl) -propenone

Pentane-2,4-dione 10.3 mL (0.1 mol) was diluted with AcOH and cooled to 0 ° C. 6.9 g (0.1 mol) of NaNO ₂ was dissolved in 10 mL of water and added dropwise to the above solution so that the internal temperature was kept at 10 ° C. or less. The mixture was stirred for 1 hour under cooling followed by 3 hours at room temperature. 14 mL (0.11 mol) of ethyl acetoacetate was dissolved in 100 mL of a 1: 1 AcOH / water solution, and 7.19 g (0.11 mol) of zinc powder was added. The mixture obtained by adding the oxime solution thereto was heated at 100 ° C. for 30 minutes and then poured into 0.8 L of water. This aqueous solution was extracted with EtOAc (3 × 500 mL). The organic extracts were combined, washed (brine), dried (MgSO ₄ ), filtered and evaporated in vacuo. The residue was purified by SiO ₂ chromatography (heptane / EtOAc gradient elution) to give 5-acetyl-2,4-dimethyl--1H- pyrrole-3-carboxylic acid ethyl ester (4.32 g). 3.5 g (16.7 mmol) of the resulting compound was added to an aqueous solution of KOH (4.22 g (75.3 mmol) dissolved in 5 mL of water, and the mixture was heated for 18 hours at 130 ° C. The mixture was then heated. Cooled, diluted with water (50 mL) and oxidized with 2 M aqueous hydrochloric acid, the mixture was extracted with EtOAc (3 × 50 mL), the organic extracts were combined, dried (MgSO ₄ ), Filter and evaporate the solvent under vacuum, purify the residue by SiO ₂ chromatography (EtOAc) to give 1.05 g of 1- (3,5-dimethyl-1H-pyrrol-2-yl) -ethanone. The obtained 1- (3,5-dimethyl-1H-pyrrol-2-yl) -ethanone (536 mg, 3.9 mmol) was replaced with nitrogen gas in a flask containing N, N-dimethylphenol. Suspended in 1.2 mL (8.8 mmol) of muamidodimethyl acetal and heated for 48 h at 90 ° C. The mixture was allowed to cool and triturated in cold EtOAc, and the resulting precipitate was filtered and washed with EtOAc Washing gave 444 mg of the pale yellow title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.41 (s, 3H, CH ₃ ), 2.23 (s, 3H, CH ₃ ), 2.23 (br, s, 6H, CH ₃ ), 4.77 (d, 1H, J = 12.4 Hz, CH), 4.95 (s, 1H, pyrrolyl-H), 6.85 (d, 1H, J = 12.4 Hz, CH).

[4- (3,5-Dimethyl-1H-pyrrol-2-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine (Compound 45)
3-Dimethylamino-1- (3,5-dimethyl-1H-pyrrol-2-yl) -propenone 125 mg (0.65 mmol), 4-fluorophenylguanidine nitrate 211 mg (0.98 mmol), and K ₂ CO ₃ 149 mg (1.08 mmol) was partially dissolved in 2-methoxyethanol and heated at 120 ° C. for 18 hours. The mixture was concentrated in vacuo and purified by SiO ₂ chromatography (heptane / EtOAc gradient elution 5-g Isolute ST ^™ cartridge). This crude product was powdered in iPr ₂ O to give 158 mg of the title compound as a pale yellow solid.
M.M. p. 168.4-171.5 ° C., MS: [M + H] ⁺ = 283.9 (C ₁₆ H ₁₅ FN ₄ requires 282.3). ¹ H-NMR (CDCl ₃ ) δ: 2.30 (s, 3H, CH ₃ ), 2.35 (s, 3H, CH ₃ ), 5.85 (s, 1H, pyrrolyl-H), 6.83 (D, 1H, J = 5.6 Hz, pyrimidinyl-H), 6.87 (br, s, 1H, NH), 7.05 (t, 2H, J = 8.5 Hz, Ph-H), 7. 51-7.54 (m, 2H, Ph-H), 8.26 (d, 1H, J = 5.4 Hz, pyrimidinyl-H), 9.08 (br.s, 1H, NH).

  3-Dimethylamino-1- (1,2,4-trimethyl-1H-pyrrol-3-yl) -propenone

818 mg (14.6 mmol) of KOH was partially dissolved in 15 mL of DMSO and stirred for 5 minutes. 1 g (7.3 mmol) of 1- (2,4-dimethyl-1H-pyrrol-3-yl) -ethanone was added in small portions and the resulting mixture was stirred for 45 minutes. 0.54 mL (8.75 mmol) of iodomethane was added dropwise at such a rate that the internal temperature was kept below 30 ° C. The mixture was stirred for an additional 45 minutes, poured into 50 mL water and extracted with Et ₂ O (3 × 60 mL). The organic extracts are combined, washed (brine), dried (MgSO ₄ ), filtered and evaporated in vacuo to give 1- (1,2,4-trimethyl-1H-pyrrol-3-yl) -ethanone 1 0.06 g was obtained as a pink solid. This was suspended in 3.6 mL (17.5 mmol) of 1,1-bis-dimethylamino-3,3-dimethyl-butan-2-one in a nitrogen-substituted flask and heated at 70 ° C. for 36 hours. The mixture was evaporated under vacuum and the residue was triturated in EtOAc. 973 mg of the title compound was obtained as a reddish solid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.30 (s, 3H, CH ₃ ), 1.51 (s, 3H, CH ₃ ), 2.20 (br.s, 6H, CH ₃ ), 2.66 (s, 3H, CH ₃ ), 4.57 (d, 1H, J = 12.5 Hz, CH), 5.53 (s, 1H, pyrrole-H), 6.72 (d, 1H, J = 12.7 Hz, CH).

4- (Fluoro-phenyl)-[4- (1,2,4-trimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (Compound 46)
150 mg (0.73 mmol) 3-dimethylamino-1- (1,2,4-trimethyl-1H-pyrrol-3-yl) -propenone, 189 mg (0.87 mmol) 4-fluorophenylguanidine nitrate, and K ₂ CO ₃ 144 mg (1.04 mmol) was partially dissolved in 3 mL of 2-methoxyethanol and heated at 110 ° C. for 36 hours. The mixture was concentrated in vacuo and purified by SiO ₂ chromatography (heptane / EtOAc gradient elution). Recrystallization from iPr ₂ O / heptane yielded 20 mg of the title compound as a brownish solid.
M.M. p. 124.2-128.3 ° C., MS: [M + H] ⁺ = 298.4 (C ₁₇ H ₁₇ FN ₄ requires 296.3). ¹ H-NMR (CDCl ₃ ) δ: 2.21 (s, 3H, CH ₃ ), 2.42 (s, 3H, CH ₃ ), 3.51 (s, 3H, CH ₃ ), 6.40 ( s, 1H, pyrrolyl-H), 6.76 (d, 1H, J = 5.4 Hz, pyrimidinyl-H), 7.01 (t, 2H, J = 8.8 Hz, Ph-H), 7.58. ~ 7.61 (m, 2H, Ph-H), 7.70 (br.s, 1H, NH), 8.28 (d, 1H, J = 5.6 Hz, pyrimidinyl-H).

3-Dimethylamino-1- (2,4-dimethyl-5-nitro-1H-pyrrol-3-yl) -propenone

HNO ₃ 69% w / v aqueous solution 0.28 mL (4.37 mmol) was added dropwise to Ac ₂ O 5 mL at room temperature with the internal temperature kept below 25 ° C. The nitration mixture was stirred at room temperature for 15 minutes and then cooled to -40 ° C. 1- (2,4-Dimethyl-1H-pyrrol-3-yl) -ethanone 500 mg (3.64 mmol) was dissolved in 6 mL of Ac ₂ O, and the internal temperature was kept at −30 ° C. or lower to form the above solution. Added dropwise. The resulting mixture was stirred at −40 ° C. for 30 minutes and at −10 ° C. for an additional 30 minutes. The mixture was poured into 50 mL ice water and extracted with Et ₂ O (3 × 60 mL). The organic extracts were combined, washed, dried (Na ₂ SO ₄ ), filtered and the solvent was evaporated under vacuum to give a dark brown solid. This was recrystallized from MeOH to obtain 158 mg of 1- (2,4-dimethyl-5-nitro-1H-pyrrol-3-yl) -ethanone. 150 mg (0.82 mmol) of the obtained compound was suspended in 0.42 mL (2.02 mmol) of 1,1-bis-dimethylamino-3,3-dimethyl-butan-2-one in a nitrogen-substituted flask, Heated at 70 ° C. for 18 hours. This mixture was triturated in EtOAc to give 119 mg of the title compound as a brown solid.
¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (s, 3H, CH ₃ ), 2.40 (s, 3H, CH ₃ ), 2.80 (br.s, 3H, CH ₃ ), 3.07 (br.s, 3H, CH ₃ ), 5.19 (d, 1H, J = 12.7 Hz, CH), 7.45 (d, 1H, J = 12.4 Hz, CH), 12. 76 (br, 1H, NH).

[4- (2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine (Compound 47)
3-dimethylamino-1- (2,4-dimethyl-5-nitro-1H-pyrrol-3-yl) -propenone 110 mg (0.46 mmol), 4-fluorophenylguanidine nitrate 150 mg (0.7 mmol), and K 193 mg (1.4 mmol) of ₂ CO ₃ was partially dissolved in 2-methoxyethanol and heated at 120 ° C. for 18 hours. The mixture was concentrated in vacuo and purified by SiO ₂ chromatography (heptane / EtOAc gradient elution). This crude product was triturated in iPr ₂ O to give 22 mg of the title compound as a pale orange solid.
M.M. p. 166.3-170.1 ° C., MS: [M + H] ⁺ = 329.3 (C ₁₆ H ₁₄ FN ₅ O ₂ requires 327.3). ¹ H-NMR (DMSO-d ₆ ) δ: 2.49 (s, 3H, CH ₃ ), 2.59 (s, 3H, CH ₃ ), 6.73 (d, 1H, J = 5.1 Hz, Pyrimidinyl-H), 7.04 (t, 2H, J = 8.8 Hz, Ph-H), 7.07 (br.s, 1H, NH), 7.55 to 7.58 (m, 2H, Ph) -H), 8.44 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 9.40 (br.s, 1H, NH).

  The following compounds were prepared in a similar manner as described above.

N- [4- (2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl) -pyrimidin-2-yl] -N ′, N′-dimethyl-benzene-1,4-diamine (Compound 48 )
M.M. p. 265-268 ° C., MS: [M + H] ⁺ = 353.0 (C ₁₈ H ₂₀ N ₆ O ₂ requires 352.4). ¹ H-NMR (DMSO-d ₆ ) δ: 2.39 (s, 3H, CH ₃ ), 2.48 (br.s, 6H, CH ₃ ), 2.82 (s, 3H, CH ₃ ), 6.69 (d, 2H, J = 9.0 Hz, Ph-H), 6.74 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 7.50 (d, 2H, J = 9. 0 Hz, Ph-H), 8.38 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 9.18 (s, 1H, NH), 13.00 (br.s, 1H, NH).

[4- (5-Amino-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine (Compound 49)
45 mg (0.14 mmol) of [4- (2,4-dimethyl-5-nitro-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine was dissolved in 3 mL of EtOH. 10 mg of 10% Pd (C) catalyst was added, followed by 48 μL (0.84 mmol) of hydrazine hydrate 55% w / w aqueous solution. The mixture was heated at reflux for 18 hours. After cooling, the mixture was filtered using a pad of Celite filter aid and the filtrate was evaporated under vacuum. The residue was purified by SiO ₂ chromatography (EtOAc / 2M ammonia MeOH solution 20: 1) to give 14 mg of the title compound as a yellow solid.
M.M. p. ^{227-231 ℃, MS: [M +} H] + = 397.8 (C 16 H 16 FN 5 requires 297.3). ¹ H-NMR (CDCl ₃ ) δ: 1.98 (s, 3H, CH ₃ ), 2.37 (s, 3H, CH ₃ ), 4.86 (br.s, 2H, NH ₂ ), 6. 65 (d, 1H, J = 4.9 Hz, pyrimidinyl-H), 7.03 (t, 2H, J = 8.3 Hz, Ph-H), 7.49 (br.s, 2H, NH), 7 58-7.61 (m, 2H, Ph-H), 8.53 (d, 1H, J = 4.9 Hz, pyrimidinyl-H).

[4- (5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine (Compound 50)
80 mg (0.28 mmol) of [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine was dissolved in THF (4 mL), Cooled to -50 ° C. 55 mg (0.31 mmol) of N-bromosuccinimide was dissolved in 2 mL of THF, and added dropwise to the above while keeping the internal temperature at −40 ° C. or lower. The mixture was stirred for 1 hour under cooling and then evaporated under vacuum. The residue was treated with 10 mL of water and extracted with EtOAc (3 × 10 mL). The organic extracts were combined, washed, dried (MgSO ₄ ), filtered and evaporated in vacuo. The crude product was purified by SiO ₂ chromatography (heptane / EtOAc gradient elution) and recrystallized from iPr ₂ O to give 19 mg of the title compound as an orange solid.
M.M. p. 181.4-183.3 ° C., MS: [M + H] ⁺ = 362.9 (C ₁₆ H ₁₄ BrFN ₄ requires 361.2). ¹ H-NMR (CDCl ₃ ) δ: 2.10 (s, 3 H, CH ₃ ), 2.36 (s, 3 H, CH ₃ ), 6.56 (d, 1 H, J = 5.1 Hz, pyrimidinyl- H), 6.97 (t, 2H, J = 8.3 Hz, Ph-H), 7.00 (br.s, 1H, NH), 7.79 to 7.52 (m, 2H, Ph-H) ), 8.85 (br.s, 1H, NH), 8.26 (d, 1H, J = 5.1 Hz, pyrimidinyl-H).

  The following compounds were prepared in a similar manner.

[4- (5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(3-nitro-phenyl) -amine (Compound 51)
M.M. p. 198.1-203 ° C., MS: [M + H] ⁺ = 389.3 (C ₁₆ H ₁₄ BrN ₅ O ₄ requires 361.2). ¹ H-NMR (CDCl ₃ ) δ: 2.49 (s, 3 H, CH ₃ ), 2.59 (s, 3 H, CH ₃ ), 6.73 (d, 1 H, J = 5.1 Hz, pyrimidinyl- H), 7.04 (t, 2H, J = 8.8 Hz, Ph-H), 7.57 (m, 2H, Ph-H), 7.90 (br.s, 1H, NH), 8. 44 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 9.40 (br.s, 1H, NH).

[4- (5-Chloro-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine (Compound 52)
80 mg (0.28 mmol) of [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine was dissolved in 4 mL of THF, and -60 ° C. Cooled to. 41 mg (0.31 mmol) of N-chlorosuccinimide was dissolved in 2 mL of THF, and added dropwise to the above so that the internal temperature was kept at −50 ° C. or lower. The mixture was stirred under cooling for 30 minutes and then evaporated under vacuum. The residue was treated with 10 mL of water and extracted with EtOAc (3 × 10 mL). The organic extracts were combined, washed, dried (MgSO ₄ ), filtered and evaporated in vacuo. The crude product was purified by SiO ₂ chromatography (heptane / EtOAc gradient elution) and recrystallized from iPr ₂ O to give 37 mg of the title compound as an orange solid.
M.M. p. ^{200-203 ℃, MS: [M +} H] + = 317.7 (C 16 H 14 ClF- 4 requires 316.8). ¹ H-NMR (CDCl ₃ ) δ: 2.17 (s, 3 H, CH ₃ ), 2.42 (s, 3 H, CH ₃ ), 6.77 (d, 1 H, J = 5.9 Hz, pyrimidinyl- H), 7.02-7.06 (m, 3H, Ph-H, NH), 7.54-7.56 (m, 2H, Ph-H), 7.95 (br.s, 1H, NH) ), 8.25 (d, 1H, J = 5.4 Hz, pyrimidinyl-H).

[4- (5-Diethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine (Compound 53)
Diethylamine 40 μL (0.31 mmol) was diluted with methanol (0.5 mL), and formaldehyde 37% w / w aqueous solution 30 μL (0.37 mmol) was added. 87 mg (0.31 mmol) of [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine are added in small portions and the mixture is heated. Refluxed. After 1.5 hours, the mixture was diluted with 10 mL of water. The resulting precipitate was filtered and powdered in 2M aqueous hydrochloric acid. The mixture was filtered and the filtrate was washed with 2M aqueous sodium hydroxide. The filtrate was extracted with EtOAc (3 × 15 mL). The organic extracts were combined, washed, dried (MgSO ₄ ), filtered and evaporated in vacuo. The crude product was purified by SiO ₂ chromatography (heptane / EtOAc gradient elution) and recrystallized from iPr ₂ O to give 36 mg of the title compound as an orange solid.
M.M. p. 71.9-74.2 ° C., MS: [M + H] ⁺ = 367.7 (C ₂₁ H ₂₆ FN ₅ requires 367.5). ¹ H-NMR (CD ₃ OD) δ: 1.10 (t, 6H, J = 7.1 Hz, CH ₃ ), 2.19 (s, 3H, CH ₃ ), 2.41 (s, 3H, CH _{3), 2.58 (t, 4H} , J = 7.8Hz, CH 2), 3.56 (s, 2H, CH 2), 6.78 (d, 1H, J = 5.6Hz, pyrimidinyl -H ), 7.00 (t, 2H, J = 8.5 Hz, Ph-H), 7.61-7.63 (m, 2H, Ph-H), 8.22 (d, 1H, J = 5. 4 Hz, pyrimidinyl-H).

  The following compounds were prepared in a similar manner.

[4- (5-Dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine (Compound 54)
M.M. p. 88.4-91.6 ° C., MS: [M + H] ⁺ = 340.6 (C ₁₉ H ₂₂ FN ₅ requires 339.4). ¹ H-NMR (CDCl ₃ ) δ: 2.18 (s, 3H, CH ₃ ), 2.56 (s, 6H, CH ₃ ), 2.42 (s, 3H, CH ₃ ), 3.38 ( _{s, 2H, CH 2),} 6.75 (d, 1H, J = 5.4Hz, pyrimidinyl -H), 7.00 (t, 2H , J = 8.6Hz, Ph-H), 7.13 ( br.s, 1H, NH), 7.56-7.59 (m, 2H, Ph-H), 8.31 (d, 1H, J = 5.1 Hz, pyrimidinyl-H), 8.55 (br .S, 1H, NH).

[4- (2,4-Dimethyl-5-morpholin-4-ylmethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine (Compound 55)
M.M. p. 94.7-97.6 ° C., MS: [M + H] ⁺ = 382.1 (C ₂₁ H ₂₄ FN ₅ O requires 381.5). ¹ H-NMR (DMSO-d ₆ ) δ: 2.12 (s, 3H, CH ₃ ), 2.33-2.35 (m, 7H, CH ₃ , CH ₂ ), 3.55 (m, 4H , CH ₂ ), 4.03 (s, 2H, CH ₂ ), 6.73 (d, 1H, J = 5.4 Hz, pyrimidinyl-H), 7.08 (t, 2H, J = 9.0 Hz, Ph-H), 7.74-7.78 (m, 2H, Ph-H), 8.28 (d, 1H, J = 5.4 Hz, pyrimidinyl-H), 9.27 (s, 1H, NH) ), 10.76 (s, 1H, NH).

[4- [2,4-Dimethyl-5- (4-methyl-piperazin-1-ylmethyl) -1H-pyrrol-3-yl] -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine ( Compound 56)
M.M. p. ^{120.4-123.1 ℃, MS: [M +} H] + = 396.4 (C 22 H 27 FN 5 requires 394.5). ¹ H-NMR (CDCl ₃ ) δ: 1.62 (br.s, 4H, CH ₂ ), 2.10 (s, 3H, CH ₃ ), 2.34 (s, 3H, CH ₃ ), 2. _{37 (s, 3H, CH 3} ), 2.43 (br.s, 4H, CH 2), 3.42 (s, 2H, CH 2), 6.67 (d, 1H, J = 5.4Hz, Pyrimidinyl-H), 6.91-6.96 (m, 3H, Ph-H, NH), 7.50-7.52 (m, 2H, Ph-H), 8.24 (d, 1H, J = 5.4 Hz, pyrimidinyl-H), 8.30 (br.s, 1H, NH).

Kinase specificity of selected compounds Kinase selectivity of compounds selected from the above examples was examined. A protein kinase population containing CDK suitable for the present invention and a representative example of a functionally unrelated kinase were used.

Assays for CDK4 / cyclin D1, CDK2 / cyclin E, CDK1 / cyclin B kinase were performed by observing phosphorylation of GST-Rb in the preferred system. Therefore, phosphorylation of GST-Rb induced by CDK4 / cyclin D1, CDK2 / cyclin E, or CDK1 / cyclin B was performed using GST-Rb (772-928) using radiolabeled ATP in a 96-well format in vitro kinase assay. ) Was measured by the radioisotope-labeled phosphoric acid incorporated into. The phosphorylation reaction mixture (total amount 40 μl) was 50 mM HEPES (pH 7.4), 20 mM MgCl ₂ , 5 mM EGTA, 2 mM DTT, 20 mM β-glycerophosphate, 2 mM NaF, 1 mM Na ₃ VO ₄ , Protease Inhibitors Cocktail (manufactured by Sigma). , See above), 0.5 mg / ml BSA, 1 μg purified enzyme complex, 10 μl GST-Rb-Sepharose beads, 100 μM ATP, 0.2 μCi ³² P-ATP. The mixture was constantly shaken and reacted at 30 ° C. for 30 minutes. At the end of this reaction period, 100 μl of 50 mM HEPES (pH 7.4) and 1 mM ATP were added to each well, and the entire amount was transferred to a GFC filter plate. The plate was washed 5 times with 200 μl of 50 mM HEPES (pH 7.4) and 1 mM ATP. 50 μl of scintillation liquid was added to each well, and the radioactivity of the sample was measured with a scintillation counter (Topcount, manufactured by HP). IC ₅₀ values for various peptides were calculated using GraFit software.

Alternatively, CDK2 / cyclin A kinase assay may be performed on 96-well plates using recombinant CDK2 / cyclin A. To assay buffer consisting of 25 mM β-glycerophosphate, 20 mM MOPS, 5 mM EGTA, 1 mM DTT, 1 mM NaVO ₃ , pH 7.4, 2-4 μg of CDK2 / cyclin A along with the substrate pRb (773-928) was added. The reaction was started by adding Mg / ATP mixture (15 mM MgCl ₂ , 100 μM ATP containing 30-50 kBq of [γ- ³² P] -ATP per well), and these mixtures were added at 30 ° C. as needed. Incubated for ~ 30 minutes. The reaction was stopped on ice and filtered using a p81 filter plate (Whatman Polyfiltronics, Kent, UK). After washing 3 times with 75 mM orthophosphoric acid, the plate was dried, a scintillation fluid was added, and the incorporated radioactivity was measured with a scintillation counter (TopCount, Packard Instruments, Pangbourne, Berks, UK).

PKCα kinase activity may be measured by looking at the incorporation of radiolabeled phosphate into histone 3, as described below. The reaction mixture (total volume 65 μl) was 50 mM Tris-HCl, 1 mM calcium acetate, 3 mM DTT, 0.03 mg / ml phosphatidylserine, 2.4 μg / ml PMA, 0.04% NP40, 12 mM Mg / Cl, purified PKCα100 ng 0.2 mg / ml histone 3, 100 μM ATP, 0.2 μCi [γ- ³² P] -ATP. The reaction was run for 15 minutes at 37 ° C. in a microplate shaker, stopped by adding 10 μl of 75 mM orthophosphoric acid, and the plate was placed on ice. Transfer 50 μl of this reaction mixture to a P81 filter plate, wash away free radioactive phosphate (3 times with 200 μl of 75 mM orthophosphoric acid per well), add 50 μl of scintillation fluid (Microscint 40) to each well, and The activity was measured with a scintillation counter (Topcount, HP).

CDK2 and / or PKC used in the above assay may be obtained from available materials or may be made by recombinant methods as described below. His-tagged CDK2 / cyclin E and CDK1 / cyclin B were co-expressed and PKCα was expressed alone in Sf9 insect cells infected with the appropriate baculovirus construct. These cells were recovered by low speed centrifugation 2 days after infection, and the protein was purified from the insect cell pellet by metal-chelate chromatography. Briefly, the insect cell pellet was sonicated and buffered in buffer A (10 mM Tris-HCl (pH 8.0), 150 mM NaCl, 0.02% NP40 and 5 mM β-marcaptoethanol, 1 mM NaF, 1 mM Na ₃ VO ₄ , and AEBSF, pepstatin A, E64, bestatin, leupeptin (Protease Inhibitors Cocktail (manufactured by Sigma)). The soluble fraction was removed by centrifugation and transferred onto Ni-NTA-agarose (Quiagen). Unbound protein was washed away with 300 mM NaCl, 5-15 mM imidazole in buffer A, and bound protein was eluted with 250 mM imidazole in buffer A. The purified protein is carefully dialyzed against storage buffer (20 mM HEPES (pH 7.4), 50 mM NaCl, 2 mM DTT, 1 mM EDTA, 1 mM EGTA, 0.02% NP40, 10% v / v glycerol) and aliquoted. And stored at -70 ° C. Purification of PKC-α-6 × His is carried out in the same manner as described above, but using a different buffer (50 mM NaH ₂ PO ₄ (pH 8.0) instead of Tris, 0.000 instead of NP40). 05% Triton X-100).

  The results in Table 1 below show that each corresponding compound has a high selectivity for CDK inhibition.

Anti-proliferative effects of selected compounds The compounds selected from the above examples were subjected to standard cell proliferation assays using various human tumor cell lines. A standard 72 hour MTT (thiazolyl blue; 3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide) assay was performed (Haselsberger, K .; Peterson, DC; Thomas , DG; Darling, JL Anti Cancer Drugs 1996, 7, 331-8; Loveland, BE; Johns, TG; Mackay, IR; Vaillant, F .; Wang, ZX; Hertzog, PJ Biochemistry International 1992, 27, 501-10 ). Human tumor cell lines were obtained from ATCC (American Type Culture Collection, 10801 University Boulevard, Manessas, VA 20110-2209, USA).

  The results in Table 2 illustrate the antiproliferative effects of the compounds described in this application.

FIG. 2 shows a chemical structure of a compound according to the present invention.

Claims (33)

Formula (I)
[Wherein ^one of X ¹ and X ^{2 represents} NH , and the other represents CR ⁹ ;
Z represents NH, NHCO, NHSO ₂ , NHCH ₂ , CH ₂ , CH ₂ CH ₂ , or CH═CH;
R ¹ , R ² , R ³ and R ⁹ are each independently a hydrogen atom, alkyl, aryl, aralkyl, heterocycle, halogeno, NO ₂ , CN, OH, alkoxy, aryloxy, (R ′ ″) nNH ₂ , (R ''')nNH-R', (R ''') nN- (R') (R ''), NH-aryl, N- (aryl) ₂ , COOH, COO-R ', COO - _{aryl, CONH 2, CONH-R '} , CON- (R') (R ''), CONH- aryl, CON- _{(aryl) 2, SO 3 H, SO} 2 NH 2, CF 3, CO-R ' or CO- aryl are shown (alkyl, aryl, aralkyl, and each group of heterocycles are further selected halogeno, NO _2, CN, OH, O-methyl, NH _2, COOH, CONH _2, and CF ₃ may be substituted with one or more groups), this Here, at least one group of R ¹ , R ² and R ⁹ represents a group other than a hydrogen atom ;
R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently a hydrogen atom, substituted or unsubstituted lower alkyl, halogeno, NO ₂ , CN, OH, substituted or unsubstituted alkoxy, NH ₂ , NH-R ', N- (R ') (R ''), COOH, COO-R ', CONH 2, CONH-R', CON- (R ') (R''), SO 3 H, SO 2 Represents NH ₂ or CF ₃ ;
R ', R''andR''' each independently represent the same or different alkyl group, n Ru 0 or 1 der. And a pharmaceutically acceptable salt thereof. X ¹ and X ² represent CR ⁹ and NH, respectively;
R ¹ , R ² , R ³ and R ⁹ are each independently a hydrogen atom, alkyl, aryl, aralkyl, heterocycle, halogeno, NO ₂ , CN, OH, alkoxy, aryloxy, (R ′ ″) nNH _{2, (R ''')}nNH-R', (R ''') nN- (R') (R ''), COOH, COO-R ', CONH 2, CONH-R', CON- (R ′) (R ″), SO ₃ H, SO ₂ NH ₂ , CF ₃ , and CO—R ′ (alkyl, aryl and aralkyl groups are further halogeno, NO ₂ , CN, OH, O - methyl _{(O-methyl), NH 2} , COOH, optionally substituted with one or more groups selected from CONH ₂ and CF _3);
Z is selected from NH, NHSO ₂ and NHCH ₂ ;
R ^{4 to} R ⁸ are each independently a hydrogen atom, halogeno, nitro, amino, aminoalkyl, hydroxy, alkoxy, carbamoyl, sulfamyl, N (R ′) (R ″), C _1-4 alkyl, and substituted 2. The compound according to claim 1, wherein the compound is selected from _C1-4 alkyl. ^3. The compound according to 1 or 2, wherein Z is NH and R ³ is a hydrogen atom. R ¹ , R ² and R ⁹ are each independently a hydrogen atom, halogeno, CN, NO ₂ , CO (NH ₂ ), (R ′ ″) NH (R ′) (R ″), C ₁₋ The compound according to claim 3, wherein the compound represents a ₄ alkyl group or a heterocyclic group. When R ¹ is halogeno, it is selected from chloro or bromo; when R ¹ is alkylamino, it represents diethylaminomethyl or dimethylaminomethyl; when R ¹ is a heterocycle, morpholin-4-ylmethyl Or a compound according to claim 4, characterized in that it represents 4-methyl-piperazin-1-ylmethyl. The compound according to any one of claims 1 to 5, wherein R ¹ represents a hydrogen atom or CN, and R ² and R ⁹ are both methyl. The compound according to claim 6, wherein R ¹ is a hydrogen atom. The compound according to claim 6, wherein R ¹ is CN. R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each independently a hydrogen atom, unsubstituted lower alkyl, halogeno, NO ₂ , CN, OH, N— (R ′) (R ″) Or CF ₃ ;
9. The compound according to claim 1, wherein R ′, R ″ and R ″ ′ each independently represent the same or different alkyl group, and n is 0 or 1. . R ^{4 to} R ⁸ are each independently selected from a hydrogen atom, F, NH ₂ , NO ₂ , OH, Cl, Br, I, CN, CH ₂ OH, CF ₃ and dimethylamino. 10. A compound according to claim 9. The compound according to claim 9 or 10, wherein R ⁴ and R ⁸ are both hydrogen atoms. 2- [N- (phenyl)]-4- (2,4-dimethylpyrrol-3-yl) pyrimidinamine, wherein the phenyl group is in the 2, 3, 4 or 5 position, F, _{NH 2, NO 2, OH,} Cl, Br, I, CN, CH 2 OH, a compound according to any one of claims 1 to 11, characterized in that they have been substituted with at least one of CF ₃ or OMe . The phenyl group is mono-substituted at any of the 2, 3, 4 or 5 positions with F, NH ₂ , NO ₂ , OH, Cl, Br, I, CH ₂ OH, CN, CF ₃ or OMe, or Disubstituted with 2,4-difluoro, 3,5-difluoro, 3,4-difluoro, 2,4-dichloro, 3,5-dichloro, 3,4-dichloro, or 4-chloro-3-trifluoromethyl The compound according to claim 12, wherein 2- [N- (phenyl)]-4- (3,5-dimethyl-1H-pyrrole-2-carbonitrile) pyrimidinamine, wherein the phenyl group is in the 2, 3 or 4 position, _{F, NH (CH 3) 2} , NO 2, OH, Cl, Br, I, or a compound according to any one of claims 1 to 11, characterized in that it is substituted with at least one CF _3. The phenyl group is mono-substituted with F, NH (CH ₃ ) ₂ , NO ₂ , OH, I, or CF ₃ at either the 3 or 4 position, or 4-methyl-3-nitro, 3-iodo 6. Disubstituted with -4-methyl, 4-chloro-3-methyl, 3-hydroxy-4-methyl, 4-fluoro-3-methyl, or 4-methyl-3-fluoro. 14. The compound according to 14. 2- [N- (phenyl)]-4- (2,4-dimethyl-5-nitro-1H-pyrrol-3-yl) -pyrimidinamine, wherein the phenyl group is in the 4-position; _{F, NH (CH 3) 2} , NO 2, OH,, or a compound according to any one of claims 1 to 5, characterized in that is monosubstituted by CF _3. The compound according to claim 16, wherein the phenyl group is substituted at the 4-position with a fluoro group or an NH (CH ₃ ) ₂ group. A compound selected from 2- [N- (phenyl)]-4- (2,4-dimethyl-5-halogeno-1H-pyrrol-3-yl) -pyrimidinamine, wherein the phenyl group is in the 3 or 4 position The compound according to claim 1, wherein the compound is monosubstituted by F, NH (CH ₃ ) ₂ , NO ₂ , OH, I, or CF ₃ . 19. A compound according to claim 18, characterized in that the phenyl group is substituted at the 3 or 4 position with a 4-fluoro or 3-nitro group and the halogeno is chloro or bromo. A compound selected from 2- [N- (phenyl)]-4- (2,4-dimethyl-5-dialkylaminoalkyl-1H-pyrrol-3-yl) -pyrimidinamine, wherein the phenyl group is in the 4-position The compound according to claim 1, wherein the compound is monosubstituted by F, NH (CH ₃ ) ₂ , NO ₂ , OH, I, or CF ₃ . 21. A compound according to claim 20, characterized in that the phenyl group is substituted with fluoro and the dialkylaminoalkyl group is preferably diethylaminomethyl or dimethylaminomethyl. In a compound selected from 2- [N- (phenyl)]-4- (2,4-dimethyl-5- (heterocyclic) -1H-pyrrol-3-yl) -pyrimidinamine, the phenyl group is in the 4-position _{, F, NH (CH 3)} 2, NO 2, OH, I, or a compound according to any one of claims 1 to 5, characterized in that is monosubstituted by CF _3. 23. The compound according to claim 22, wherein the phenyl group is substituted with fluoro and the heterocyclic group is 5-morpholin-4-ylmethyl or 4-methyl-piperazin-1-ylmethyl. [4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrole-3 -Yl) -pyrimidin-2-yl]-(3-nitro-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-iodo) -Phenyl) -amine (3,4-difluoro-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (4-chloro-phenyl)- [4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (3,5-difluoro-phenyl)-[4- (2,4-dimethyl-1H-pyrrole) -3-yl) -pyrimidin-2-y ] -Amine 4- [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-ylamino] -phenol 3- [4- (2,4-dimethyl-1H-pyrrole-3- Yl) -pyrimidin-2-ylamino] -phenol (2,4-difluoro-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (2 , 4-Dichloro-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (4-chloro-3-trifluoromethyl-phenyl)-[ 4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl ]-(4-Triff Oromethyl-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(3-trifluoromethyl-phenyl) -amine (3-chloro-phenyl) -[4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine N- [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidine -2-yl] -N ′, N′-dimethyl-benzene-1,4-diamine (3-chloro-4-iodo-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) ) -Pyrimidin-2-yl] -amine [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(3-fluoro-4-iodo-phenyl) -amine 3 , 5-Dimethyl-4- [2- 3-nitro-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile 4- [2- (4-fluoro-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl- 1H-pyrrole-2-carbonitrile 4- [2- (4-hydroxy-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 3,5-dimethyl-4 -[2- (4-Trifluoromethyl-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile 4- [2- (4-iodo-phenylamino) -pyrimidin-4-yl] 3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-hydroxy-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl- 1H-pyrrole-2-carbonitrile 3,5-dimethyl-4- [2- (4-methyl-3-nitro-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile 4- [ 2- (3-Iodo-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-chloro-3-methyl- Phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-hydroxy-4-methyl-phenylamino) -pyrimidin-4-yl]- 3,5-Dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole Ru-2-carbonitrile 4- [2- (3-Fluoro-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-Dimethylamino-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-fluoro-phenylamino) -pyrimidin-4-yl ] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid amide [4- (3,5-dimethyl-1H-pyrrol-2-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) - Amin
[ 4- (2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine N- [4- (2,4-dimethyl -5-nitro-1H-pyrrol-3-yl) -pyrimidin-2-yl] -N ', N'-dimethyl-benzene-1,4-diamine [4- (5-amino-2,4-dimethyl- 1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (5-bromo-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidine- 2-yl]-(4-fluoro-phenyl) -amine [4- (5-bromo-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(3-nitro-phenyl) ) -Amine [4- (5-Chloro-2,4-dimethyl) Ru-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (5-diethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl) -Pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (5-dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-( 4-Fluoro-phenyl) -amine [4- (2,4-dimethyl-5-morpholin-4-ylmethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl)- Amine
From [4- [2,4-dimethyl-5- (4-methyl-piperazin-1-ylmethyl) -1H-pyrrol-3-yl] -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine 2. The compound of claim 1 selected. [4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrole-3 -Yl) -pyrimidin-2-yl]-(3-nitro-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-iodo) -Phenyl) -amine (3,4-difluoro-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (4-chloro-phenyl)- [4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine (3,5-difluoro-phenyl)-[4- (2,4-dimethyl-1H-pyrrole) -3-yl) -pyrimidin-2-y ] -Amine 4- [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-ylamino] -phenol 3- [4- (2,4-dimethyl-1H-pyrrole-3- Yl) -pyrimidin-2-ylamino] -phenol [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-trifluoromethyl-phenyl) -amine (3 -Chloro-4-iodo-phenyl)-[4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl] -amine [4- (2,4-dimethyl-1H-pyrrole) -3-yl) -pyrimidin-2-yl]-(3-fluoro-4-iodo-phenyl) -amine 3,5-dimethyl-4- [2- (3-nitro-phenylamino) -pyrimidin-4- Il] -1H- Roll-2-carbonitrile 4- [2- (4-fluoro-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-hydroxy -Phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 3,5-dimethyl-4- [2- (4-trifluoromethyl-phenylamino) -pyrimidine- 4-yl] -1H-pyrrole-2-carbonitrile 4- [2- (4-iodo-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-Hydroxy-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 3,5-dimethyl-4- [2- (4-Methyl-3-nitro-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile 4- [2- (3-iodo-4-methyl-phenylamino) -pyrimidine-4- Yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-chloro-3-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H- Pyrrole-2-carbonitrile 4- [2- (3-hydroxy-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-fluoro-4-methyl-) Enylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-dimethylamino-phenylamino) -pyrimidin-4-yl] -3,5- dimethyl -1H- pyrrole-4- [2- (4-fluoro - phenylamino) - pyrimidin-4-yl] -3,5-dimethyl--1H- pyrrole-2-carboxylic acid ami de
[ 4- (2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine N- [4- (2,4-dimethyl -5-nitro-1H-pyrrol-3-yl) -pyrimidin-2-yl] -N ', N'-dimethyl-benzene-1,4-diamine [4- (5-bromo-2,4-dimethyl- 1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (5-bromo-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidine- 2-yl]-(3-nitro-phenyl) -amine [4- (5-chloro-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) ) -Amine [4- (5-Diethylaminomethyl) -2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (5-dimethylaminomethyl-2,4-dimethyl-1H- Pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (2,4-dimethyl-5-morpholin-4-ylmethyl-1H-pyrrol-3-yl)- Pyrimidin-2-yl]-(4-fluoro-phenyl) -amine, and {4- [2,4-dimethyl-5- (4-methyl-piperazin-1-ylmethyl) -1H-pyrrol-3-yl] 25. A compound according to claim 24, selected from -pyrimidin-2-yl}-(4-fluoro-phenyl) -amine. [4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrole-3 -Yl) -pyrimidin-2-yl]-(3-nitro-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-iodo) -Phenyl) -amine [4- (2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-trifluoromethyl-phenyl) -amine 3,5-dimethyl-4- [2- (3-Nitro-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile 4- [2- (4-fluoro-phenylamino) -pyrimidin-4-yl] -3, 5-Dimethyl-1H-pi 2-carbonitrile 4- [2- (4-hydroxy-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 3,5-dimethyl-4- [2- (4-Trifluoromethyl-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile 4- [2- (4-iodo-phenylamino) -pyrimidin-4-yl]- 3,5-Dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-hydroxy-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 3 , 5-Dimethyl-4- [2- (4-methyl-3-nitro-phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile 4- [2- (3-yo Do-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-chloro-3-methyl-phenylamino) -pyrimidine -4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-hydroxy-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl -1H-pyrrole-2-carbonitrile 4- [2- (4-fluoro-3-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (3-Fluoro-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-dimethylamino No-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-fluoro-phenylamino) -pyrimidin-4-yl] -3, 5-Dimethyl-1H-pyrrole-2-carboxylic acid amide [4- (2,4-dimethyl-5-nitro-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) Amine N- [4- (2,4-dimethyl-5-nitro-1H-pyrrol-3-yl) -pyrimidin-2-yl] -N ′, N′-dimethyl-benzene-1,4-diamine [ 4- (5-Bromo-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (5-bromo-2,4- Dimethyl-1H-pyrrole-3- ) -Pyrimidin-2-yl]-(3-nitro-phenyl) -amine [4- (5-chloro-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-( 4-Fluoro-phenyl) -amine [4- (5-diethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4 -(5-dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine, and [4- (2,4-dimethyl) 26. A compound according to claim 25 selected from -5-morpholin-4-ylmethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine. [4- (2,4-Dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-(3-nitro-phenyl) -amine [4- (2,4-dimethyl-1H-pyrrole-3 -Yl) -pyrimidin-2-yl]-(4-iodo-phenyl) -amine 3,5-dimethyl-4- [2- (3-nitro-phenylamino) -pyrimidin-4-yl] -1H-pyrrole 2-carbonitrile 4- [2- (4-fluoro-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2- (4-hydroxy- Phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 3,5-dimethyl-4- [2- (4-trifluoromethyl-phenylamino) -pyrimidine-4 Yl] -1H-pyrrole-2-carbonitrile 4- [2- (4-iodo-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 4- [2 -(3-Hydroxy-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carbonitrile 3,5-dimethyl-4- [2- (4-methyl-3-nitro) -Phenylamino) -pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile 4- [2- (3-hydroxy-4-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl -1H-pyrrole-2-carbonitrile 4- [2- (4-fluoro-3-methyl-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2- Rubonitrile 4- [2- (4-Fluoro-phenylamino) -pyrimidin-4-yl] -3,5-dimethyl-1H-pyrrole-2-carboxylic acid amide [4- (2,4-dimethyl-5-nitro -1H-pyrrol-3-yl) -pyrimidin-2-yl]-(4-fluoro-phenyl) -amine [4- (5-bromo-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidine -2-yl]-(3-nitro-phenyl) -amine, and [4- (5-dimethylaminomethyl-2,4-dimethyl-1H-pyrrol-3-yl) -pyrimidin-2-yl]-( 27. A compound according to claim 26 selected from 4-fluoro-phenyl) -amine. X ¹ and X ² represent NH and CR ⁹ respectively;
R ¹ , R ² , R ³ and R ⁹ are each independently a hydrogen atom, alkyl, aryl, aralkyl, heterocycle, halogeno, NO ₂ , CN, OH, alkoxy, aryloxy, (R ′ ″) nNH _{2, (R ''')}nNH-R', (R ''') nN- (R') (R ''), COOH, COO-R ', CONH 2, CONH-R', CON- (R ′) (R ″), SO ₃ H, SO ₂ NH ₂ , CF ₃ , and CO—R ′ (alkyl, aryl and aralkyl groups are further halogeno, NO ₂ , CN, OH, O - methyl _{(O-methyl), NH 2} , COOH, optionally substituted with one or more groups selected from CONH ₂ and CF _3);
Z is selected from NH, NHSO ₂ and NHCH ₂ ;
R ⁴ , R ⁵ and R ⁸ are each independently a hydrogen atom, halogeno, nitro, amino, aminoalkyl, hydroxy, alkoxy, carbamoyl, sulfamyl, N (R ′) (R ″), C _1-4 alkyl And substituted C _1-4 alkyl;
R ⁶ is selected from a hydrogen atom, halogeno, nitro, amino, aminoalkyl, hydroxy, alkoxy, carbamoyl, sulfamyl, N (R ′) (R ″), methyl, propyl, butyl, and substituted C _1-4 alkyl Is;
R ⁷ is selected from a hydrogen atom, halogeno, nitro, amino, aminoalkyl, hydroxy, carbamoyl, sulfamyl, N (R ′) (R ″), C _2-4 alkyl, and substituted C _1-4 alkyl The compound according to claim 1, wherein A pharmaceutical composition comprising a compound as defined in any of claims 1 to 28 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient. A proliferative disease therapeutic agent comprising as an active ingredient the compound defined in any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof. The therapeutic agent according to claim 30, wherein the proliferative disease is cancer or leukemia. The therapeutic agent according to claim 30 or 31, characterized in that it contains a sufficient amount of the compound to inhibit at least one CDK enzyme. The therapeutic agent according to claim 32, wherein the CDK enzyme is CDK2 and / or CDK4.